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Homologies between SARS-CoV-2 and allergen proteins may direct T cell-mediated heterologous immune responses. Scientific reports Balz, K., Kaushik, A., Chen, M., Cemic, F., Heger, V., Renz, H., Nadeau, K., Skevaki, C. 2021; 11 (1): 4792
Abstract

The outbreak of the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a public health emergency. Asthma does not represent a risk factor for COVID-19 in several published cohorts. We hypothesized that the SARS-CoV-2 proteome contains T cell epitopes, which are potentially cross-reactive to allergen epitopes. We aimed at identifying homologous peptide sequences by means of two distinct complementary bioinformatics approaches. Pipeline 1 included prediction of MHC Class I and Class II epitopes contained in the SARS-CoV-2 proteome and allergens along with alignment and elaborate ranking approaches. Pipeline 2 involved alignment of SARS-CoV-2 overlapping peptides with known allergen-derived T cell epitopes. Our results indicate a large number of MHC Class I epitope pairs including known as well as de novo predicted allergen T cell epitopes with high probability for cross-reactivity. Allergen sources, such as Aspergillus fumigatus, Phleum pratense and Dermatophagoides species are of particular interest due to their association with multiple cross-reactive candidate peptides, independently of the applied bioinformatic approach. In contrast, peptides derived from food allergens, as well as MHC class II epitopes did not achieve high in silico ranking and were therefore not further investigated. Our findings warrant further experimental confirmation along with examination of the functional importance of such cross-reactive responses.

View details for DOI 10.1038/s41598-021-84320-8

View details for PubMedID 33637823
SARS-CoV-2 infection and COVID-19 in asthmatics: a complex relationship. Nature reviews. Immunology Skevaki, C., Karsonova, A., Karaulov, A., Fomina, D., Xie, M., Chinthrajah, S., Nadeau, K. C., Renz, H. 2021
View details for DOI 10.1038/s41577-021-00516-z

View details for PubMedID 33623123
Innate Lymphoid Cells: The Missing Part Of A Puzzle In Food Allergy. Allergy Sahiner, U. M., Layhadi, J. A., Golebski, K., Istvan Komlosi, Z., Peng, Y., Sekerel, B., Durham, S. R., Brough, H., Morita, H., Akdis, M., Turner, P., Nadeau, K., Spits, H., Akdis, C., Shamji, M. H. 2021
Abstract

Food allergy is an increasingly prevalent disease which is mainly driven by uncontrolled type 2 immune response. Currently, knowledge about the underlying mechanisms that initiate and promote the immune response to dietary allergens is limited. Patients with food allergy are commonly sensitized through the skin in their early life, later on developing allergy symptoms within the gastrointestinal tract. Food allergy results from a dysregulated type 2 response to food allergens, characterized by enhanced levels of IgE, IL-4, IL-5 and IL-13 with infiltration of mast cells, eosinophils and basophils. Recent studies raised a possible role for the involvement of innate lymphoid cells (ILCs) in driving food allergy. They represent a group of lymphocytes that lack specific, recombined antigen receptors. ILCs contribute to immune responses not only by releasing cytokines and other mediators but also by responding to cytokines produced by activated cells in their local microenvironment. Due to their localization at barrier surfaces ofthe airways, gut and skin, ILCs form a link between the innate and adaptive immunity. This review summarizes recent evidence on how skin and gastrointestinal mucosal immune system contribute to both homeostasis and the development of food allergy, as well as the involvement of ILCs towards inflammatory processes and regulatory mechanisms.

View details for DOI 10.1111/all.14776

View details for PubMedID 33583026
Traffic-related Air Pollution is Associated with Glucose Dysregulation, Blood Pressure, and Oxidative Stress in Children. Environmental research Mann, J. K., Lutzker, L., Holm, S. M., Margolis, H. G., Neophytou, A. M., Eisen, E. A., Costello, S., Tyner, T., Holland, N., Tindula, G., Prunicki, M., Nadeau, K., Noth, E. M., Lurmann, F., Hammond, S. K., Balmes, J. R. 2021: 110870
Abstract

BACKGROUND: Metabolic syndrome increases the risk of cardiovascular disease in adults. Antecedents likely begin in childhood and whether childhood exposure to air pollution plays a contributory role is not well understood.OBJECTIVES: To assess whether children's exposure to air pollution is associated with markers of risk for metabolic syndrome and oxidative stress, a hypothesized mediator of air pollution-related health effects.METHODS: We studied 299 children (ages 6-8) living in the Fresno, CA area. At a study center visit, questionnaire and biomarker data were collected. Outcomes included hemoglobin A1c (HbA1c), urinary 8-isoprostane, systolic blood pressure (SBP), and BMI. Individual-level exposure estimates for a set of four pollutants that are constituents of traffic-related air pollution (TRAP) - the sum of 4-, 5-, and 6-ring polycyclic aromatic hydrocarbon compounds (PAH456), NO2, elemental carbon, and fine particulate matter (PM2.5) - were modeled at the primary residential location for 1-day lag, and 1-week, 1-month, 3-month, 6-month, and 1-year averages prior to each participant's visit date. Generalized additive models were used to estimate associations between each air pollutant exposure and outcome.RESULTS: The study population was 53% male, 80% Latinx, 11% Black and largely low-income (6% were White and 3% were Asian/Pacific Islander). HbA1c percentage was associated with longer-term increases in TRAP; for example a 4.42 ng/m3 increase in 6-month average PAH456 was associated with a 0.07% increase (95% CI: 0.01, 0.14) and a 3.62 mug/m3 increase in 6-month average PM2.5 was associated with a 0.06% increase (95% CI: 0.01, 0.10). The influence of air pollutants on blood pressure was strongest at 3 months; for example, a 6.2 ppb increase in 3-month average NO2 was associated with a 9.4 mmHg increase in SBP (95% CI: 2.8, 15.9). TRAP concentrations were not significantly associated with anthropometric or adipokine measures. Short-term TRAP exposure averages were significantly associated with creatinine-adjusted urinary 8-isoprostane.DISCUSSION: Our results suggest that both short- and longer-term estimated individual-level outdoor residential exposures to several traffic-related air pollutants, including ambient PAHs, are associated with biomarkers of risk for metabolic syndrome and oxidative stress in children.

View details for DOI 10.1016/j.envres.2021.110870

View details for PubMedID 33587949
COVID-19 Patients Seeking Treatment: Modeling Predictive Age-dependent and Independent Symptoms and Comorbidities. Journal of medical Internet research Huang, Y., Radenkovic, D., Perez, K., Nadeau, K., Verdin, E., Furman, D. 2021
Abstract

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to ravage and burden hospitals around the world. The epidemic started in Wuhan, China was recognized by the World Health Organization (WHO) as an international public health emergency and declared the outbreak a pandemic in March 2020. Since then, the scale of disruptions caused by the COVID-19 pandemic is having an unparalleled effect in recent history.OBJECTIVE: With increasing total hospitalization and Intensive Care Unit (ICU) admissions, a better understanding of features related to patients with COVID-19 could help healthcare workers stratify patients based on the risk of developing more severe diseases. Using predictive models, we strive to select features that are the most relevant to more severe COVID-19 diseases.METHODS: Over 3 million participants have reported their potential symptoms of COVID-19 along with their comorbidities, demographics and symptoms on a smartphone-based app. Using the >10,000 individuals who indicated that they were tested positive in the United Kingdom, we leveraged Elastic Net regularized binary classifier to derive predictors that are most correlated with users having severe enough disease to seek treatment in a hospital setting. We then analyzed such features in relation to age and other demographics and their longitudinal trend.RESULTS: The most predictive features found include fever, the use of immunosuppressant medication, use of mobility aid, shortness of breath, and fever. Such features are age-related and some are manifesting disproportionally in minority populations.CONCLUSIONS: Predictors selected from the predictive models can be used to stratify patients into groups that may need more attention than others. It could help health care workers to devote valuable resources to prevent the escalation of diseases in vulnerable populations.CLINICALTRIAL:

View details for DOI 10.2196/25696

View details for PubMedID 33621185
Fecal microbiome and metabolome differ in healthy and food-allergic twins. The Journal of clinical investigation Bao, R., Hesser, L. A., He, Z., Zhou, X., Nadeau, K. C., Nagler, C. R. 2021; 131 (2)
Abstract

BACKGROUNDThere has been a striking generational increase in the prevalence of food allergies. We have proposed that this increase can be explained, in part, by alterations in the commensal microbiome.METHODSTo identify bacterial signatures and metabolic pathways that may influence the expression of this disease, we collected fecal samples from a unique, well-controlled cohort of twins concordant or discordant for food allergy. Samples were analyzed by integrating 16S rRNA gene amplicon sequencing and liquid chromatography-tandem mass spectrometry metabolite profiling.RESULTSA bacterial signature of 64 operational taxonomic units (OTUs) distinguished healthy from allergic twins; the OTUs enriched in the healthy twins were largely taxa from the Clostridia class. We detected significant enrichment in distinct metabolite pathways in each group. The enrichment of diacylglycerol in healthy twins is of particular interest for its potential as a readily measurable fecal biomarker of health. In addition, an integrated microbial-metabolomic analysis identified a significant association between healthy twins and Phascolarctobacterium faecium and Ruminococcus bromii, suggesting new possibilities for the development of live microbiome-modulating biotherapeutics.CONCLUSIONTwin pairs exhibited significant differences in their fecal microbiomes and metabolomes through adulthood, suggesting that the gut microbiota may play a protective role in patients with food allergies beyond the infant stage.TRIAL REGISTRATIONParticipants in this study were recruited as part of an observational study (ClinicalTrials.gov NCT01613885) at multiple sites from 2014 to 2018.FUNDINGThis work was supported by the Sunshine Charitable Foundation; the Moss Family Foundation; the National Institute of Allergy and Infectious Diseases (NIAID) (R56AI134923 and R01AI 140134); the Sean N. Parker Center for Allergy and Asthma Research; the National Heart, Lung, and Blood Institute (R01 HL 118612); the Orsak family; the Kepner family; and the Stanford Institute for Immunity, Transplant and Infection.

View details for DOI 10.1172/JCI141935

View details for PubMedID 33463536
Aging and CMV discordance are associated with increased immune diversity between monozygotic twins. Immunity & ageing : I & A Yan, Z., Maecker, H. T., Brodin, P., Nygaard, U. C., Lyu, S. C., Davis, M. M., Nadeau, K. C., Andorf, S. 2021; 18 (1): 5
Abstract

BACKGROUND: Broadly, much of variance in immune system phenotype has been linked to the influence of non-heritable factors rather than genetics. In particular, two non-heritable factors: aging and human cytolomegavirus (CMV) infection, have been known to account for significant inter-individual immune variance. However, many specific relationships between them and immune composition remain unclear, especially between individuals over narrower age ranges. Further exploration of these relationships may be useful for informing personalized intervention development.RESULTS: To address this need, we evaluated 41 different cell type frequencies by mass cytometry and identified their relationships with aging and CMV seropositivity. Analyses were done using 60 healthy individuals, including 23 monozygotic twin pairs, categorized into young (12-31years) and middle-aged (42-59years). Aging and CMV discordance were associated with increased immune diversity between monozygotic twins overall, and particularly strongly in various T cell populations. Notably, we identified 17 and 11 cell subset frequencies as relatively influenced and uninfluenced by non-heritable factors, respectively, with results that largely matched those from studies on older-aged cohorts. Next, CD4+ T cell frequency was shown to diverge with age in twins, but with lower slope than in demographically similar non-twins, suggesting that much inter-individual variance in this cell type can be attributed to interactions between genetic and environmental factors. Several cell frequencies previously associated with memory inflation, such as CD27- CD8+ T cells and CD161+ CD4+ T cells, were positively correlated with CMV seropositivity, supporting findings that CMV infection may incur rapid aging of the immune system.CONCLUSIONS: Our study confirms previous findings that aging, even within a relatively small age range and by mid-adulthood, and CMV seropositivity, both contribute significantly to inter-individual immune diversity. Notably, we identify several key immune cell subsets that vary considerably with aging, as well as others associated with memory inflation which correlate with CMV seropositivity.

View details for DOI 10.1186/s12979-021-00216-1

View details for PubMedID 33461563
EAACI statement on the diagnosis, management and prevention of severe allergic reactions to COVID-19 vaccines. Allergy Sokolowska, M., Eiwegger, T., Ollert, M., Torres, M. J., Barber, D., Del Giacco, S., Jutel, M., Nadeau, K. C., Palomares, O., Rabin, R. L., Riggioni, C., Vieths, S., Agache, I., Shamji, M. H. 2021
Abstract

The first approved COVID-19 vaccines include Pfizer/BioNTech BNT162B2, Moderna mRNA-1273 and AstraZeneca recombinant adenoviral ChAdOx1-S. Soon after approval, severe allergic reactions to the mRNA-based vaccines that resolved after treatment were reported. Regulatory agencies from the European Union, Unites States and the United Kingdom agree that vaccinations are contraindicated only when there is an allergy to one of the vaccine components or if there was a severe allergic reaction to the first dose. This position paper of the European Academy of Allergy and Clinical Immunology (EAACI) agrees with these recommendations and clarifies that there is no contraindication to administer these vaccines to allergic patients who do not have a history of an allergic reaction to any of the vaccine components. Importantly, as is the case for any medication, anaphylaxis may occur after vaccination in the absence of a history of allergic disease. Therefore, we provide a simplified algorithm of prevention, diagnosis and treatment of severe allergic reactions and a list of recommended medications and equipment for vaccine centres. We also describe potentially allergenic/immunogenic components of the approved vaccines and propose a workup to identify the responsible allergen. Close collaboration between academia, regulatory agencies and vaccine producers will facilitate approaches for patients at risks, such as incremental dosing of the second injection or desensitisation. Finally, we identify unmet research needs and propose a concerted international roadmap towards precision diagnosis and management to minimise the risk of allergic reactions to COVID-19 vaccines and to facilitate their broader and safer use.

View details for DOI 10.1111/all.14739

View details for PubMedID 33452689
Targeted DNA methylation profiling reveals epigenetic signatures in peanut allergy. JCI insight Zhou, X., Han, X., Lyu, S. C., Bunning, B. J., Kost, L., Chang, I., Cao, S., Sampath, V., Nadeau, K. C. 2021
Abstract

DNA methylation (DNAm) has been shown to play a role in mediating food allergy, however, the mechanism by which it does so is poorly understood. In this study, we used targeted NextGen bisulfite sequencing to evaluate DNAm levels in 125 targeted highly informative genomic regions containing 602 CpG sites on 70 immune-related genes to understand whether DNAm can differentiate peanut allergy (PA) vs non-allergy (NA). We found PA-associated DNAm signatures associated with 12 genes (7 novel to food allergy, 3 associated with Th1/Th2, and 2 associated with innate immunity) as well as DNAm signature combinations with superior diagnostic potential compared to serum peanut specific-IgE for PA vs. NA. Further, we found that following peanut protein stimulation, peripheral blood mononuclear cell (PBMCs) from PA participants showed increased production of cognate cytokines compared to NA participants. The varying responses between PA and NA participants may be associated with the interaction between the modification of DNAm and the interference of environment. Using Euclidean distance analysis, we found that the distances of methylation profile comprising 12 DNAm signatures between PA and NA pairs in monozygotic (MZ) twins were smaller than that in randomly paired genetically unrelated individuals, suggesting that PA related DNAm signatures may be associated with genetic factors.

View details for DOI 10.1172/jci.insight.143058

View details for PubMedID 33571165
Air pollution exposure is linked with methylation of immunoregulatory genes, altered immune cell profiles, and increased blood pressure in children. Scientific reports Prunicki, M., Cauwenberghs, N., Lee, J., Zhou, X., Movassagh, H., Noth, E., Lurmann, F., Hammond, S. K., Balmes, J. R., Desai, M., Wu, J. C., Nadeau, K. C. 2021; 11 (1): 4067
Abstract

Ambient air pollution exposure is associated with cardiovascular dysregulation and immune system alterations, yet no study has investigated both simultaneously in children. Understanding the multifaceted impacts may provide early clues for clinical intervention prior to actual disease presentation. We therefore determined the associations between exposure to multiple air pollutants and both immunological outcomes (methylation and protein expression of immune cell types associated with immune regulation) and cardiovascular outcomes (blood pressure) in a cohort of school-aged children (6-8�years; n?=?221) living in a city with known elevated pollution levels. Exposure to fine particular matter (PM2.5), carbon monoxide (CO), and ozone (O3) was linked to altered methylation of most CpG sites for genes Foxp3, IL-4, IL-10 and IFN-g, all involved in immune regulation (e.g. higher PM2.5 exposure 1�month prior to the study visit was independently associated with methylation of the IL-4 CpG24 site (est?=?0.16; P?=?0.0095). Also, immune T helper cell types (Th1, Th2 and Th17) were associated with short-term exposure to PM2.5, O3 and CO (e.g. Th1 cells associated with PM2.5 at 30�days: est?=?-�0.34, P?
View details for DOI 10.1038/s41598-021-83577-3

View details for PubMedID 33603036
A novel patient-reported outcomes instrument assessing the side effects of peanut oral immunotherapy. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology Turner-Bowker, D. M., Jalbert, J. J., Krohe, M., Yaworsky, A., Kelly, M. T., Padilla, B., Chaston, E., Radin, A., Mastey, V., Nadeau, K. C. 2021; 126 (1): 61?68
Abstract

BACKGROUND: Patients treated with peanut oral immunotherapy (OIT) may experience adverse reactions, particularly during up-dosing.OBJECTIVE: To develop the Side Effects of Peanut Oral Immunotherapy Diary (SEPOD), an electronic questionnaire assessing the daily side effects of peanut OIT in clinical trials.METHODS: Content and design of the SEPOD were informed by empirical literature review and meetings with 3 allergy-immunology experts. Interviews to confirm content and inform revisions were conducted in 24 pediatric patients with peanut allergy (14 treated with peanut OIT) aged 6 to 17 years; children aged 6 to 11years were interviewed with their caregiver.RESULTS: The SEPOD was drafted after literature review and expert interviews; the initial measurement approach comprised 2 SEPOD versions, a patient-reported outcome (PRO) version for children aged 12 to 17 years, and a caregiver-administered PRO version for children aged 6 to 11 years with instructions for caregiver questionnaire administration. Pediatric patients were expected to respond independently on both versions. Patient interviews indicated that some younger children (ie, aged 6-8 years) had difficulty understanding questions, even when reading aloud; therefore, a caregiver-administered outcome version, identical in content to the caregiver-administered PRO version, was developed for this age group. The final electronic SEPOD covered 23 peanut OIT side effects within the following 7 domains: gastrointestinal, dermatologic, itching, nasal, and respiratory, swelling (eyelid or periorbital, lip, tongue, and throat), pain (tongue, mouth, and throat), and dizziness.CONCLUSION: This study yielded the SEPOD, a new clinical outcome assessment instrument with various methods of administration that can be used to assess the side effects of peanut OIT experienced by pediatric patients in a clinical trial setting.

View details for DOI 10.1016/j.anai.2020.07.027

View details for PubMedID 32745610
Basophil activation test shows high accuracy in the diagnosis of peanut and tree nut allergy: The Markers of Nut Allergy Study. Allergy Duan, L., Celik, A., Hoang, J. A., Schmidthaler, K., So, D., Yin, X., Ditlof, C. M., Ponce, M., Upton, J. E., Lee, J., Hung, L., Breiteneder, H., Palladino, C., Atkinson, A. R., Kim, V. H., Berenjy, A., Asper, M., Hummel, D., Wong, S., Alexanian-Farr, M., Magder, A., Chinthrajah, S. R., Mukai, K., Tsai, M., Nadeau, K., Galli, S. J., Ramani, A. K., Szepfalusi, Z., Eiwegger, T. 2020
Abstract

BACKGROUND: Peanut and tree nut allergies are the most important causes of anaphylaxis. Co-reactivity to more than one nut is frequent, and co-sensitization in the absence of clinical data is often obtained. Confirmatory oral food challenges (OFCs) are inconsistently performed.OBJECTIVE: To investigate the utility of the basophil activation test (BAT) in diagnosing peanut and tree nut allergy.METHODS: The Markers Of Nut Allergy Study (MONAS) prospectively enrolled patients aged 0.5-17 years with confirmed peanut and/or tree nut (almond, cashew, hazelnut, pistachio, walnut) allergy or sensitization fromCanadian (n=150) and Austrian (n=50) tertiary pediatric centers. BAT using %CD63+ basophils (SSClow/CCR3pos) as outcome was performed with whole blood samples stimulated with allergen extracts of each nut (0.001-1000ng/mL protein). BAT results were assessed against confirmed allergic status in a blinded fashion to develop a generalizable statistical model for comparisonto extract and marker allergen-specificIgE.RESULTS: A mixed effect model integrating BAT results for 10 and 100 ng/mL of peanut and individual tree nut extracts was optimal. The area under the ROC curve (AUROC) was 0.98 for peanut, 0.97 for cashew, 0.92 for hazelnut, 0.95 for pistachio, and 0.97 for walnut. The BAT outperformed sIgE testing for peanut or hazelnut and was comparable for walnut (AUROC 0.95, 0.94, 0.92) ina sub-analysis in sensitized patients undergoing OFC.CONCLUSIONS: BAT can predict allergic clinical status to peanut and tree nuts in multi-nut sensitized children and may reduce the need for high-risk OFCs in patients.

View details for DOI 10.1111/all.14695

View details for PubMedID 33300157
Addressing Climate Change and Its Effects on Human Health: A Call to Action for Medical Schools. Academic medicine : journal of the Association of American Medical Colleges Goshua, A., Gomez, J., Erny, B., Burke, M., Luby, S., Sokolow, S., LaBeaud, A. D., Auerbach, P., Gisondi, M. A., Nadeau, K. 2020
Abstract

Human health is increasingly threatened by rapid and widespread changes in the environment and climate, including rising temperatures, air and water pollution, disease vector migration, floods, and droughts. In the United States, many medical schools, the American Medical Association, and the National Academy of Sciences have published calls for physicians and physicians-in-training to develop a basic knowledge of the science of climate change and an awareness of the associated health risks. The authors--all medical students and educators--argue for the expeditious redesign of medical school curricula to teach students to recognize, diagnose, and treat the many health conditions exacerbated by climate change as well as understanding public health issues. In this Invited Commentary, the authors briefly review the health impacts of climate change, examine current climate change course offerings and proposals, and describe the rationale for promptly and comprehensively including climate science education in medical school curricula. Efforts in training physicians now will benefit those physicians' communities, whose health will be impacted by a period of remarkable climate change. The bottom line is that the health effects of climate reality cannot be ignored, and people everywhere must adapt as quickly as possible.

View details for DOI 10.1097/ACM.0000000000003861

View details for PubMedID 33239537
Mass Cytometry Phenotyping of Human Granulocytes Reveals Novel Basophil Functional Heterogeneity. iScience Vivanco Gonzalez, N., Oliveria, J., Tebaykin, D., Ivison, G. T., Mukai, K., Tsai, M. M., Borges, L., Nadeau, K. C., Galli, S. J., Tsai, A. G., Bendall, S. C. 2020; 23 (11): 101724
Abstract

Basophils, the rarest granulocyte, play critical roles in parasite- and allergen-induced inflammation. We applied mass cytometry (CyTOF) to simultaneously asses 44 proteins to phenotype and functionally characterize neutrophils, eosinophils, and basophils from 19 healthy donors. There was minimal heterogeneity seen in eosinophils and neutrophils, but data-driven analyses revealed four unique subpopulations within phenotypically basophilic granulocytes (PBG; CD45+HLA-DR-CD123+). Through CyTOF and fluorescence-activated cell sorting (FACS), we classified these four PBG subpopulations as (I) CD16lowFcepsilonRIhighCD244high (88.5� 1.2%), (II) CD16highFcepsilonRIhighCD244high (9.1� 0.4%), (III) CD16lowFcepsilonRIlowCD244low (2.3� 1.3), and (IV) CD16highFcepsilonRIlowCD244low (0.4� 0.1%). Prospective isolation confirmed basophilic-morphology of PBG I-III, but neutrophilic-morphology of PBG IV. Functional interrogation via IgE-crosslinking or IL-3 stimulation demonstrated that PBG I-II had significant increases in CD203c expression, whereas PBG III-IV remained unchanged compared with media-alone conditions. Thus, PBG III-IV could serve roles in non-IgE-mediated immunity. Our findings offer new perspectives in human basophil heterogeneity and the varying functional potential of these new subsets in health and disease.

View details for DOI 10.1016/j.isci.2020.101724

View details for PubMedID 33205028
Inhibition of CpG methylation improves the barrier integrity of bronchial epithelial cells in asthma. Allergy Wawrzyniak, P., Krawczyk, K., Acharya, S., Tan, G., Wawrzyniak, M., Karouzakis, E., Dreher, A., Jakiela, B., Altunbulakli, C., Sanak, M., O'Mahony, L., Nadeau, K., Akdis, C. A. 2020
View details for DOI 10.1111/all.14667

View details for PubMedID 33210726
Grass pollen immunotherapy alters chromatin landscape in circulating T follicular and regulatory cells. The Journal of allergy and clinical immunology Sharif, H., Acharya, S., Dhondalay, G. K., Varricchi, G., Krasner-Macleod, S., Laisuan, W., Switzer, A., Lenormand, M., Kashe, E., Parkin, R. V., Yi, Y., Koc, M., Fedina, O., Vila-Nadal, G., Marone, G., Eifan, A., Scadding, G. W., Fear, D. J., Nadeau, K. C., Durham, S. R., Shamji, M. H. 2020
Abstract

BACKGROUND: Allergen-specific immunotherapy (AIT) is a disease-modifying treatment that induces long-term T cell tolerance.OBJECTIVE: To evaluate the role of circulating CXCR5+PD-1+T follicular helper (cTFH) and T follicular regulatory (TFR) cells following grass pollen subcutaneous (SCIT) and sublingual (SLIT) immunotherapy and the accompanying changes in their chromatin landscape.METHODS: Phenotype and function of cTFH cells were initially evaluated in grass pollen-allergics (GPA, n= 28) and non-atopic controls (NAC, n=13) by mathematical algorithms developed to manage high-dimensional data and cell culture, respectively. cTFH and TFR cells were further enumerated in NAC (n=12), GPA (n=14), SCIT (n=10) and SLIT (n=8)-treated groups. Chromatin accessibility in cTFH and TFR cells was assessed by ATAC-seq to investigate epigenetic mechanisms underlying the differences between NAC, GPA, SCIT and SLIT.RESULTS: cTFH cells were shown to be distinct from TH2 and TH2A cell subsets, capable of secreting IL-4 and IL-21. Both cytokines synergistically promoted B cell class switching to IgE and plasma cell differentiation. Grass pollen allergen induced cTFH cell proliferation in GPA but not in NAC (P<.05). cTFH cells were higher in GPA compared to NAC and were lower in SCIT and SLIT (P<.01). Time-dependent induction of IL-4, IL-21 and IL-6 were observed in nasal mucosa following intranasal allergen challenge in GPA but not in SCIT and SLIT groups. TFR and IL-10+ cTFH cells were induced in SCIT and SLIT (all, P<.01). ATAC-seq analyses revealed differentially accessible chromatin regions in all groups.CONCLUSION: For the first time, we showed dysregulation of cTFH cells in GPA compared to NAC, SCIT and SLIT and induction of TFR and IL-10+ cTFH cells following SCIT and SLIT. Changes in the chromatin landscape were observed following AIT in cTFH and TFR cells.

View details for DOI 10.1016/j.jaci.2020.10.035

View details for PubMedID 33160969
Advances and novel developments in mechanisms of allergic inflammation. Allergy Han, X., Krempski, J. W., Nadeau, K. 2020
Abstract

In the past decade, research in the molecular and cellular underpinnings of basic and clinical immunology has significantly advanced our understanding of allergic disorders, allowing scientists and clinicians to diagnose and treat disorders such as asthma, allergic and nonallergic rhinitis, and food allergy. In this review, we discuss several significant recent developments in basic and clinical research as well as important future research directions in allergic inflammation. Certain key regulatory cytokines, genes, and molecules have recently been shown to play key roles in allergic disorders. For example,interleukin-33 (IL-33)plays an important role in refractory disorders such as asthma, allergic rhinitis, and food allergy, mainly by inducing T helper (Th) 2 immune responses. Further, the cytokine TSLP has been shown to be a key factor in maintaining immune homeostasis and regulating inflammatory responses at mucosal barriers and targeting TSLP-mediated signaling is considered an attractive therapeutic strategy. We discuss interleukin 4 receptor pathways, which recently has shown to play a critical role among the allergic inflammatory pathways that drive allergic disorders and pathogenesis. The alarmin IL-33 has found to play a major role in type-2 immune responses in allergic diseases and clinical trials with IL33 inhibitors are underway in food allergy. Further, the cytokine Thymic Stromal Lymphopoietin (TSLP)has recently been shown a factor in maintaining immune homeostasis and regulating type-2 inflammatory responses at mucosal barriers in allergic inflammation. Also, new immune and genetic studies found that IL-4R pathways play a critical role among the allergic inflammatory pathways that drive allergic disorders and pathogenesis. In addition, new findings establish an important T cell-intrinsic role of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) proteolytic activity in the suppression of autoimmune responses. We have seen how mutations in the filaggrin gene are significant risk factor for allergic diseases such as atopic dermatitis, asthma, allergic rhinitis, food allergy (FA), and contact allergy and hand eczema. We are only beginning to understand the mechanisms by which the human microbiota may be regulating the immune system, and how sudden changes in the composition of the microbiota may have profound effects, linked with an increased risk of developing chronic inflammatory disorders, including allergies. New research has shown the important but complex role monocytes play in such disorders as food allergies. Finally, we discuss some of the new directions of research in this area, particularly the important use of biologicals in oral immunotherapy, advances in gene therapy, multi-food therapy, novel diagnostics in diagnosing allergic disorders, and the central role that OMICS plays in creating molecular signatures and biomarkers of allergic disorders such as food allergy. Such exciting new developments and advances has significantly moved forth our ability to understand the mechanisms underlying allergic diseases for improved patient care.

View details for DOI 10.1111/all.14632

View details for PubMedID 33068299
Immune biomarkers link air pollution exposure to blood pressure in adolescents. Environmental health : a global access science source Prunicki, M., Cauwenberghs, N., Ataam, J. A., Movassagh, H., Kim, J. B., Kuznetsova, T., Wu, J. C., Maecker, H., Haddad, F., Nadeau, K. 2020; 19 (1): 108
Abstract

BACKGROUND: Childhood exposure to air pollution contributes to cardiovascular disease in adulthood. Immune and oxidative stress disturbances might mediate the effects of air pollution on the cardiovascular system, but the underlying mechanisms are poorly understood in adolescents. Therefore, we aimed to identify immune biomarkers linking air pollution exposure and blood pressure levels in adolescents.METHODS: We randomly recruited 100 adolescents (mean age, 16years) from Fresno, California. Using central-site data, spatial-temporal modeling, and distance weighting exposures to the participant's home, we estimated average pollutant levels [particulate matter (PM), polyaromatic hydrocarbons (PAH), ozone (O3), carbon monoxide (CO) and nitrogen oxides (NOx)]. We collected blood samples and vital signs on health visits. Using proteomic platforms, we quantitated markers of inflammation, oxidative stress, coagulation, and endothelial function. Immune cellular characterization was performed via mass cytometry (CyTOF). We investigated associations between pollutant levels, cytokines, immune cell types, and blood pressure (BP) using partial least squares (PLS) and linear regression, while adjusting for important confounders.RESULTS: Using PLS, biomarkers explaining most of the variance in air pollution exposure included markers of oxidative stress (GDF-15 and myeloperoxidase), acute inflammation (C-reactive protein), hemostasis (ADAMTS, D-dimer) and immune cell types such as monocytes. Most of these biomarkers were independently associated with the air pollution levels in fully adjusted regression models. In CyTOF analyses, monocytes were enriched in participants with the highest versus the lowest PM2.5 exposure. In both PLS and linear regression, diastolic BP was independently associated with PM2.5, NO, NO2, CO and PAH456 pollution levels (P?0.009). Moreover, monocyte levels were independently related to both air pollution and diastolic BP levels (P?0.010). In in vitro cell assays, plasma of participants with high PM2.5 exposure induced endothelial dysfunction as evaluated by eNOS and ICAM-1 expression and tube formation.CONCLUSIONS: For the first time in adolescents, we found that ambient air pollution levels were associated with oxidative stress, acute inflammation, altered hemostasis, endothelial dysfunction, monocyte enrichment and diastolic blood pressure. Our findings provide new insights on pollution-related immunological and cardiovascular disturbances and advocate preventative measures of air pollution exposure.

View details for DOI 10.1186/s12940-020-00662-2

View details for PubMedID 33066786
Identification of Pru du 6 as a potential marker allergen for almond allergy. Allergy Kabasser, S., Hafner, C., Chinthrajah, S., Sindher, S. B., Kumar, D., Kost, L. E., Long, A. J., Nadeau, K. C., Breiteneder, H., Bublin, M. 2020
Abstract

BACKGROUND: Oral food challenges have demonstrated that diagnosis of almond allergy based on extract-sIgE tests display low specificity. Molecular allergy diagnosis is expected to improve accuracy, but its value in diagnosing almond allergy remains unknown.OBJECTIVE: To identify relevant almond allergens and examine their ability to improve almond allergy diagnosis.METHODS: IgE-reactive proteins were purified from almond kernels. IgE-binding to almond extract and the allergens was analyzed by quantitative ELISA using sera from 18 subjects with a proven almond allergy. The control group consisted of sera from 18 subjects allergic to peanut and/or tree nuts but tolerant to almond.RESULTS: Three IgE-binding proteins were identified: legumin (Pru du 6), alpha-hairpinin (Pru du 8) and mandelonitrile lyase (Pru du 10). Positive IgE (?0.35 kU/L) to almond extract showed 94% sensitivity but only 33% specificity. IgE to Pru du 6 maintained high sensitivity (83%) and provided superior specificity (78%). Sera from almond-allergic subjects had significantly higher IgE levels to almond extract (P<0.0001) and Pru du 6 (P<0.0001) than sera from tolerant donors. Sensitization to Pru du 6 was highly specific for almond allergy, while frequencies of sensitization to legumins from peanut, walnut, hazelnut, and cashew were similar in both groups. IgE to Pru du 8 and Pru du 10 was less sensitive (41% and 67%), but showed specificities of 100% and 61%.CONCLUSION: The use of almond allergens markedly increases the diagnostic specificity compared to the extract. Pru du 6 is a potential new molecular marker for almond allergy.

View details for DOI 10.1111/all.14613

View details for PubMedID 33020913
Biomarkers for diagnosis and prediction of therapy responses in allergic diseases and asthma ALLERGY Breiteneder, H., Peng, Y., Agache, I., Diamant, Z., Eiwegger, T., Fokkens, W. J., Traidl-Hoffmann, C., Nadeau, K., O'Hehir, R. E., O'Mahony, L., Pfaar, O., Torres, M. J., Wang, D., Zhang, L., Akdis, C. A. 2020; 75 (12): 3039?68
Abstract

Modern health care requires a proactive and individualized response to diseases, combining precision diagnosis and personalized treatment. Accordingly, the approach to patients with allergic diseases encompasses novel developments in the area of personalized medicine, disease phenotyping and endotyping, and the development and application of reliable biomarkers. A detailed clinical history and physical examination followed by the detection of IgE immunoreactivity against specific allergens still represents the state of the art. However, nowadays, further emphasis focuses on the optimization of diagnostic and therapeutic standards and a large number of studies have been investigating the biomarkers of allergic diseases, including asthma, atopic dermatitis, allergic rhinitis, food allergy, urticaria and anaphylaxis. Various biomarkers have been developed by omics technologies, some of which lead to a better classification of distinct phenotypes or endotypes. The introduction of biologicals to clinical practice increases the need for biomarkers for patient selection, prediction of outcomes and monitoring, to allow for an adequate choice of the duration of these costly and long-lasting therapies. Escalating healthcare costs together with questions about the efficacy of the current management of allergic diseases require further development of a biomarker-driven approach. Here, we review biomarkers in diagnosis and treatment of asthma, atopic dermatitis, allergic rhinitis, viral infections, chronic rhinosinusitis, food allergy, drug hypersensitivity and allergen immunotherapy with a special emphasis on specific IgE, the microbiome and the epithelial barrier. In addition, EAACI guidelines on biologicals are discussed within the perspective of biomarkers.

View details for DOI 10.1111/all.14582

View details for Web of Science ID 000573700600001

View details for PubMedID 32893900
Transcriptional changes in peanut-specific CD4+ T cells over the course of oral immunotherapy. Clinical immunology (Orlando, Fla.) Wang, W., Lyu, S., Ji, X., Gupta, S., Manohar, M., Dhondalay, G. K., Chinthrajah, S., Andorf, S., Boyd, S. D., Tibshirani, R., Galli, S. J., Nadeau, K. C., Maecker, H. T. 2020: 108568
Abstract

Oral immunotherapy (OIT) can successfully desensitize allergic individuals to offending foods such as peanut. Our recent clinical trial (NCT02103270) of peanut OIT allowed us to monitor peanut-specific CD4+ T cells, using MHC-peptide Dextramers, over the course of OIT. We used a single-cell targeted RNAseq assay to analyze these cells at 0, 12, 24, 52, and 104?weeks of OIT. We found a transient increase in TGFbeta-producing cells at 52?weeks in those with successful desensitization, which lasted until 117?weeks. We also performed clustering and identified 5 major clusters of Dextramer+ cells, which we tracked over time. One of these clusters appeared to be anergic, while another was consistent with recently described TFH13 cells. The other 3 clusters appeared to be Th2 cells by their coordinated production of IL-4 and IL-13, but they varied in their expression of STAT signaling proteins and other markers. A cluster with high expression of STAT family members also showed a possible transient increase at week 24 in those with successful desensitization. Single cell TCRalphabeta repertoire sequences were too diverse to track clones over time. Together with increased TGFbeta production, these changes may be mechanistic predictors of successful OIT that should be further investigated.

View details for DOI 10.1016/j.clim.2020.108568

View details for PubMedID 32783912
A compendium answering 150 questions on COVID-19 and SARS-CoV-2 ALLERGY Riggioni, C., Comberiati, P., Giovannini, M., Agache, I., Akdis, M., Alves-Correia, M., Anto, J. M., Arcolaci, A., Azkur, A., Azkur, D., Beken, B., Boccabella, C., Bousquet, J., Breiteneder, H., Carvalho, D., de las Vecillas, L., Diamant, Z., Eguiluz-Gracia, I., Eiwegger, T., Eyerich, S., Fokkens, W., Gao, Y., Hannachi, F., Johnston, S. L., Jutel, M., Karavelia, A., Klimek, L., Moya, B., Nadeau, K. C., O'Hehir, R., O'Mahony, L., Pfaar, O., Sanak, M., Schwarze, J., Sokolowska, M., Torres, M. J., van de Veen, W., van Zelm, M. C., Wang, D., Zhang, L., Jimenez-Saiz, R., Akdis, C. A. 2020; 75 (10): 2503?41
Abstract

In December 2019, China reported the first cases of the coronavirus disease 2019 (COVID-19). This disease, caused by the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), has developed into a pandemic. To date, it has resulted in ~9�million confirmed cases and caused almost 500�000 related deaths worldwide. Unequivocally, the COVID-19 pandemic is the gravest health and socioeconomic crisis of our time. In this context, numerous questions have emerged in demand of basic scientific information and evidence-based medical advice on SARS-CoV-2 and COVID-19. Although the majority of the patients show a very mild, self-limiting viral respiratory disease, many clinical manifestations in severe patients are unique to COVID-19, such as severe lymphopenia and eosinopenia, extensive pneumonia, a "cytokine storm" leading to acute respiratory distress syndrome, endothelitis, thromboembolic complications, and multiorgan failure. The epidemiologic features of COVID-19 are distinctive and have changed throughout the pandemic. Vaccine and drug development studies and clinical trials are rapidly growing at an unprecedented speed. However, basic and clinical research on COVID-19-related topics should be based on more coordinated high-quality studies. This paper answers pressing questions, formulated by young clinicians and scientists, on SARS-CoV-2, COVID-19, and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development, and epidemiology. A total of 150 questions were answered by experts in the field providing a comprehensive and practical overview of COVID-19 and allergic disease.

View details for DOI 10.1111/all.14449

View details for Web of Science ID 000550399700001

View details for PubMedID 32535955

View details for PubMedCentralID PMC7323196
Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19 ALLERGY Azkur, A., Akdis, M., Azkur, D., Sokolowska, M., van de Veen, W., Bruggen, M., O'Mahony, L., Gao, Y., Nadeau, K., Akdis, C. A. 2020; 75 (7): 1564?81
Abstract

As a zoonotic disease that has already spread globally to several million human beings and possibly to domestic and wild animals, eradication of coronavirus disease 2019 (COVID-19) appears practically impossible. There is a pressing need to improve our understanding of the immunology of this disease to contain the pandemic by developing vaccines and medicines for the prevention and treatment of patients. In this review, we aim to improve our understanding on the immune response and immunopathological changes in patients linked to deteriorating clinical conditions such as cytokine storm, acute respiratory distress syndrome, autopsy findings and changes in acute-phase reactants, and serum biochemistry in COVID-19. Similar to many other viral infections, asymptomatic disease is present in a significant but currently unknown fraction of the affected individuals. In the majority of the patients, a 1-week, self-limiting viral respiratory disease typically occurs, which ends with the development of neutralizing antiviral T cell and antibody immunity. The IgM-, IgA-, and IgG-type virus-specific antibodies levels are important measurements to predict population immunity against this disease and whether cross-reactivity with other coronaviruses is taking place. High viral load during the first infection and repeated exposure to virus especially in healthcare workers can be an important factor for severity of disease. It should be noted that many aspects of severe patients are unique to COVID-19 and are rarely observed in other respiratory viral infections, such as severe lymphopenia and eosinopenia, extensive pneumonia and lung tissue damage, a cytokine storm leading to acute respiratory distress syndrome, and multiorgan failure. Lymphopenia causes a defect in antiviral and immune regulatory immunity. At the same time, a cytokine storm starts with extensive activation of cytokine-secreting cells with innate and adaptive immune mechanisms both of which contribute to a poor prognosis. Elevated levels of acute-phase reactants and lymphopenia are early predictors of high disease severity. Prevention of development to severe disease, cytokine storm, acute respiratory distress syndrome, and novel approaches to prevent their development will be main routes for future research areas. As we learn to live amidst the virus, understanding the immunology of the disease can assist in containing the pandemic and in developing vaccines and medicines to prevent and treat individual patients.

View details for DOI 10.1111/all.14364

View details for Web of Science ID 000562835500003

View details for PubMedID 32396996

View details for PubMedCentralID PMC7272948
ARIA-EAACI statement on Asthma and COVID-19 (June 2, 2020). Allergy Bousquet, J., Jutel, M., Akdis, C. A., Klimek, L., Pfaar, O., Nadeau, K. C., Eiwegger, T., Bedbrook, A., Ansotegui, I. J., Anto, J. M., Bachert, C., Bateman, E. D., Bennoor, K. S., Berghea, E. C., Bergmann, K., Blain, H., Bonini, M., Bosnic-Anticevich, S., Boulet, L., Brussino, L., Buhl, R., Camargos, P., Canonica, G. W., Cardona, V., Casale, T., Chinthrajah, S., Akdis, M., Chivato, T., Christoff, G., Cruz, A. A., Czarlewski, W., Del Giacco, S., Du, H., El-Gamal, Y., Fokkens, W. J., Fonseca, J. A., Gao, Y., Gaga, M., Gemicioglu, B., Gotua, M., Haahtela, T., Halpin, D., Hamelmann, E., Hoffmann-Sommergruber, K., Humbert, M., Ilina, N., Ivancevich, J., Joos, G., Khaitov, M., Kirenga, B., Knol, E. F., Ko, F. W., Koskinen, S., Kowalski, M. L., Kraxner, H., Kudlay, D., Kuna, P., Kupczyk, M., Kvedariene, V., Abdul Latiff, A. H., Le, L. T., Levin, M., Larenas-Linnemann, D., Louis, R., Masjedi, M. R., Melen, E., Mihaltan, F., Milenkovic, B., Mohammad, Y., Morais-Almeida, M., Mullol, J., Namazova, L., Neffen, H., Nunes, E., O'Byrne, P., O'Hehir, R., O'Mahony, L., Ohta, K., Okamoto, Y., Onorato, G. L., Panzner, P., Papadopoulos, N. G., Passalacqua, G., Patella, V., Pawankar, R., Pham-Thi, N., Pigearias, B., Popov, T. A., Puggioni, F., Regateiro, F. S., Rolla, G., Rottem, M., Samolinski, B., Sastre, J., Schwarze, J., Sheikh, A., Scichilone, N., Soto-Quiros, M., Sova, M., Nicola, S., Stelmach, R., Suppli-Ulrik, C., Taborda-Barata, L., To, T., Tomazic, P., Toppila-Salmi, S., Tsiligianni, I., Usmani, O., Valiulis, A., Ventura, M. T., Viegi, G., Vontetsianos, T., Wang, D. Y., Williams, S., Wong, G. W., Yorgancioglu, A., Zernotti, M., Zidarn, M., Zuberbier, T., Agache, I. 2020
View details for DOI 10.1111/all.14471

View details for PubMedID 32588922
Food Allergy from Infancy Through Adulthood. The journal of allergy and clinical immunology. In practice Sicherer, S. H., Warren, C. M., Dant, C., Gupta, R. S., Nadeau, K. C. 2020; 8 (6): 1854?64
Abstract

Food allergies are the result of immune responses that cause adverse reactions to foods. Immune responses to foods may produce a spectrum of symptoms and disorders, including acute allergic reactions and anaphylaxis, food protein-induced allergic proctocolitis, food protein-induced enterocolitis syndrome, food-dependent, exercise-induced anaphylaxis, and oral allergy syndrome (pollen-food allergy syndrome). Food-allergic responses also contribute to chronic inflammatory disorders such as eosinophilic esophagitis and atopic dermatitis. Although food allergy affects people from infancy through adulthood, there are allergic features that differ according to age (ie, presentation, triggers, and natural course) and have important implications for diagnosis, prognosis, and management. New food allergies can develop at any age, and we propose similarities in the etiology of de novo food allergy whether in infancy or adulthood. The approach to managing food allergy changes dramatically over the life course, and physicians and patients must respond accordingly to optimize care. Food allergy therapies are emerging, and the efficacy and safety of these interventions could differ by age group of those treated. In this review, we highlight interesting observations on the etiology and characteristics of food allergy presenting at different ages and discuss clinical management as it relates to life stage.

View details for DOI 10.1016/j.jaip.2020.02.010

View details for PubMedID 32499034
Environmental factors in epithelial barrier dysfunction JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Soezener, Z., Cevhertas, L., Nadeau, K., Akdis, M., Akdis, C. A. 2020; 145 (6): 1517?28
Abstract

The main interfaces controlling and attempting to homeostatically balance communications between the host and the environment are the epithelial barriers of the skin, gastrointestinal system, and airways. The epithelial barrier constitutes the first line of physical, chemical, and immunologic defenses and provides a protective wall against environmental factors. Following the industrial revolution in the 19th century, urbanization and socioeconomic development have led to an increase in energy consumption, and waste discharge, leading to increased exposure to air pollution and chemical hazards. Particularly after the 1960s, biological and chemical insults from the surrounding environment-the exposome-have been disrupting the physical integrity of the barrier by degrading the intercellular barrier proteins at tight and adherens junctions, triggering epithelial alarmin cytokine responses such as IL-25, IL-33, and thymic stromal lymphopoietin, and increasing the epithelial barrier permeability. A�typical type 2 immune response develops in affected organs in asthma, rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, food allergy, and atopic dermatitis. The aim of this article was to discuss the effects of environmental factors such as protease enzymes of allergens, detergents, tobacco, ozone, particulate matter, diesel exhaust, nanoparticles, and microplastic on the integrity of the epithelial barriers in the context of epithelial barrier hypothesis.

View details for DOI 10.1016/j.jaci.2020.04.024

View details for Web of Science ID 000539157800004

View details for PubMedID 32507229
Increases in plasma IgG4/IgE with trilipid vs paraffin/petrolatum-based emollients for dry skin/eczema. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology Sindher, S., Alkotob, S. S., Shojinaga, M. N., Hamilton, R., Chan, S., Cao, S., Bahnson, H. T., Brough, H. A., Lack, G., Leung, D. Y., Nadeau, K. C. 2020
View details for DOI 10.1111/pai.13253

View details for PubMedID 32372469
Wildfire smoke exposure is associated with decreased methylation of the PDL2 gene Prunicki, M., Miller, S., Hopkins, A., Poulin, M., Movassagh, H., Yan, L., Nadeau, K. AMER ASSOC IMMUNOLOGISTS. 2020
View details for Web of Science ID 000589972401240
Protein- and sequencing-based massively parallel single-cell approaches to immune profiling asthma-specific cell subtypes and related gene expression biomarkers Ji, X., Acharya, S., Goncharov, I., Lyu, S., Miranda, M., Padalon-Brauch, G., Nadeau, K., Maecker, H. T. AMER ASSOC IMMUNOLOGISTS. 2020
View details for Web of Science ID 000589972401564
Phenotype consensus is required to enable large-scale genetic consortium studies of food allergy. Allergy Asai, Y., Martino, D., Eiwegger, T., Nadeau, K., Koppelman, G. H., Clarke, A. E., Lee, Y., Chan, E. S., Simons, E., Laprise, C., Mazer, B., Marenholz, I., Royce, D., Elliott, S. J., Hampson, C., Gerdts, J., Eslami, A., Soller, L., Hui, J., Azad, M., Sandford, A., Daley, D. 2020
View details for DOI 10.1111/all.14333

View details for PubMedID 32323869
Identification of cross-reactive allergens in cashew- and pistachio-allergic children during oral immunotherapy. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology He, Z., Dongre, P., Lyu, S., Manohar, M., Chinthrajah, R. S., Galli, S. J., DeKruyff, R. H., Nadeau, K. C., Andorf, S. 2020
Abstract

It has been estimated that around 8% of the children in the U.S. suffer from food allergy and of those, 40% are allergic to multiple foods. Among tree nuts, allergies to pistachios are common in those with cashew nut allergy and multiple homologous allergenic components are shared between the two nuts. Three major allergens from cashew (Ana o 1 at 50 kDa, Ana o 2 major band at 33 kDa and minor band at 53 kDa, and Ana o 3 at 10 kDa) and five major allergens from pistachio (Pis v 1 at 7 kDa, Pis v 2 at 32 kDa, Pis v 3 at 50 kDa, Pis v 4 at 23 kDa, and Pis v 5 at 36 kDa) have been identified. Of those, Ana o 1 and Pis v 3, Ana o 2 and Pis v 2, Ana o 2 and Pis v 5, Ana o 3 and Pis v 1 have been recognized as homologues based on their sequence similarity and cross reactivity to IgE from the patients.

View details for DOI 10.1111/pai.13258

View details for PubMedID 32323379
Summary of the Keystone Symposium "Origins of allergic disease: Microbial, epithelial and immune interactions,'' March 24-27, Tahoe City, California JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY DeKruyff, R. H., Zhang, W., Nadeau, K. C., Leung, D. M., Wills-Karp, M. 2020; 145 (4): 1072-+
Abstract

The aims of the Keystone Symposium conference, "Origins of allergic disease: Microbial, epithelial and immune interactions" were to present and discuss potential microbial-epithelial-immune interactions underlying the early-life origins of allergic disorders, as well as immune mechanisms that might suggest novel disease prevention or intervention strategies. Cross-talk and sharing of ideas among participating experts in basic science and clinical aspects of allergic diseases provided substantial insight into the concept of allergic disorders as a systems disease. The overriding message distilled from the discussions was that damage to epithelial surfaces lies at the origin of the various manifestations of allergic disease. The epithelium of the lungs, gut, and skin, which operates as a critical sensor of environmental stimuli, is besieged by an onslaught of contemporary environmental forces including an altered microbiome, air pollution, food allergens in a changed diet, and chemicals in modern detergents. Collectively, this onslaught leads to alterations of lung, skin, or gut epithelial surfaces, driving a type 2 immune response that underlies most, if not all, of the atopic diseases. Possible remedies for treatment and prevention of allergic diseases were discussed, including a precision medicine approach using biologics, oral desensitization, targeted gut microbiome alterations, and behavior alteration.

View details for DOI 10.1016/j.jaci.2019.11.048

View details for Web of Science ID 000523633400004

View details for PubMedID 31926182
Pilot study measuring transepidermal water loss (TEWL) in children suggests trilipid cream is more effective than a paraffin-based emollient. Allergy Sindher, S., Alkotob, S. S., Shojinaga, M. N., Brough, H. A., Bahnson, T., S, C., Lack, G., Leung, D. Y., Nadeau, K. C. 2020
View details for DOI 10.1111/all.14275

View details for PubMedID 32176320
The anti-IgE mAb omalizumab induces adverse reactions by engaging Fc gamma receptors JOURNAL OF CLINICAL INVESTIGATION Balbino, B., Herviou, P., Godon, O., Stackowicz, J., Richard-Le Goff, O., Iannascoli, B., Sterlin, D., Brule, S., Millot, G. A., Harris, F. M., Voronina, V. A., Nadeau, K. C., Macdonald, L. E., Murphy, A. J., Bruhns, P., Reber, L. L. 2020; 130 (3): 1330?35
Abstract

Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of omalizumab is associated with reported side effects ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (Fc?Rs) in Fc?R-humanized mice. We further developed an Fc-engineered mutant version of omalizumab, and demonstrated that this mAb is equally potent as omalizumab at blocking IgE-mediated allergic reactions, but does not induce Fc?R-dependent adverse reactions. Overall, our data indicate that omalizumab can induce skin inflammation and anaphylaxis by engaging Fc?Rs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions.

View details for DOI 10.1172/JCI129697

View details for Web of Science ID 000544325200031

View details for PubMedID 31770111

View details for PubMedCentralID PMC7269578
Towards personalization of asthma treatment according to trigger factors. The Journal of allergy and clinical immunology Niespodziana, K., Borochova, K., Pazderova, P., Schlederer, T., Astafyeva, N., Baranovskaya, T., Barbouche, M., Beltiukov, E., Berger, A., Borzova, E., Bousquet, J., Bumbacea, R. S., Bychkovskaya, S., Caraballo, L., Chung, K. F., Custovic, A., Docena, G., Eiwegger, T., Evsegneeva, I., Emelyanov, A., Errhalt, P., Fassakhov, R., Fayzullina, R., Fedenko, E., Fomina, D., Gao, Z., Giavina-Bianchi, P., Gotua, M., Greber-Platzer, S., Hedlin, G., Ilina, N., Ispayeva, Z., Idzko, M., Johnston, S. L., Kalayci, O., Karaulov, A., Karsonova, A., Khaitov, M., Kovzel, E., Kowalski, M. L., Kudlay, D., Levin, M., Makarova, S., Matricardi, P. M., Nadeau, K. C., Namazova-Baranova, L., Naumova, O., Nazarenko, O., O Byrne, P. M., Osier, F., Pampura, A. N., Panaitescu, C., Papadopoulos, N. G., Park, H., Pawankar, R., Pohl, W., Renz, H., Riabova, K., Sampath, V., Sekerel, B. E., Sibanda, E., Siroux, V., Sizyakina, L. P., Sun, J., Szepfalusi, Z., Umanets, T., Van Bever, H. P., van Hage, M., Vasileva, M., von Mutius, E., Wang, J., Wong, G. W., Zaikov, S., Zidarn, M., Valenta, R. 2020
Abstract

Asthma is a severe and chronic disabling disease affecting more than 300 million people world-wide. While in the past few drugs for treatment of asthma were available, new treatment options are currently emerging which appear to be highly effective in certain subgroups of patients. Accordingly there is a need for biomarkers which allow selection of patients for refined and personalized treatment strategies. Recently, serological chip tests based on micro-arrayed allergen molecules and peptides derived from the most common rhinovirus strains have been developed which may discriminate two of the most common forms of asthma, i.e., allergen- and virus-triggered asthma. In this perspective we argue that classification of asthma patients according to these common trigger factors may open new possibilities for personalized management of asthma.

View details for DOI 10.1016/j.jaci.2020.02.001

View details for PubMedID 32081759
RNA-Seq of Gastrointestinal Biopsies During Oral Immunotherapy Reveals Changes in IgA Pathway Zhang, W., Dhondalay, G., Hoh, R., Tupa, D., Bunning, B., Fernandez-Becker, N., Kambham, N., Boyd, S., Galli, S., Andorf, S., Manohar, M., Chinthrajah, S., Nadeau, K. MOSBY-ELSEVIER. 2020: AB132
View details for Web of Science ID 000517092700419
Applicability of Skin Tape Stripping Methodology In Conjunction With LC-MS/MS To Detect Topical Emollients and Drugs Used in Atopic Dermatitis Berdyshev, E., Bronova, I., Bronoff, A., Jung, J., Nadeau, K., Goleva, E., Leung, D. MOSBY-ELSEVIER. 2020: AB70
View details for Web of Science ID 000517092700216
Skin Barrier Dysfunction In Patients With Peanut Allergy Without Eczema Leung, D., Goleva, E., Hoffman, B., Bronoff, A., Jung, J., Garcia, S., Ramirez-Gama, M., Alkotob, S., Nadeau, K., Cho, C., Bronova, I., Berdyshev, E. MOSBY-ELSEVIER. 2020: AB46
View details for Web of Science ID 000517092700141
A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test Immune Markers after Minimum Maintenance Dose using Xolair Sindher, S., Kumar, D., Purington, N., Tupa, D., Long, A., Cao, S., Woch, M., Tan, T., Lloret, M., Chinthrajah, S., Nadeau, K. MOSBY-ELSEVIER. 2020: AB135
View details for Web of Science ID 000517092700429
Quality Of Life in Patients with Food Allergy: A Systematic Review and Meta-Analysis of interventions Food Allergy Diagnosis and Immunotherapy Studies Cao, S., Borro, M., Sindher, S., Tupa, D., Long, A., Chinthrajah, S., Nadeau, K., Alonzi, S. MOSBY-ELSEVIER. 2020: AB245
View details for Web of Science ID 000517092700794
The benefits of playing interactive games on virtual reality headsets during procedures in food allergy clinical trials Alonzi, S., Parikh, K., Varadharajulu, S., Chandra, S., Cao, S., Texeira, Z., Sindher, S., Nadeau, K., Chinthrajah, S. MOSBY-ELSEVIER. 2020: AB147
View details for Web of Science ID 000517092700468
Skin TEWL results show significant improvements with Trilipid emollient compared to controls in infants and young children Nadeau, K., Sindher, S., Berdyshev, E., Shojinaga, M., Alkotob, S., Alonzi, S., Varadharajulu, S., Chandra, S., Chinthrajah, S., Brough, H., Chan, S., Lack, G., Leung, D. MOSBY-ELSEVIER. 2020: AB240
View details for Web of Science ID 000517092700777
Perceived Burden of Treatment and Quality of Life in Long-Term Follow Up after Oral Immunotherapy in Food Allergic Patients Collins, W., Raeber, O., Tupa, D., Cao, S., Nadeau, K., Sindher, S., Chinthrajah, S. MOSBY-ELSEVIER. 2020: AB147
View details for Web of Science ID 000517092700470
A Qualitative Exploration of Food Allergy Management among a Medicaid-Insured Population Bozen, A., Zaslavsky, J., Cohn, D., Agnihotri, N., Davies, S., Samady, W., Lombard, L., Nadeau, K., Gupta, R., Tobin, M. MOSBY-ELSEVIER. 2020: AB86
View details for Web of Science ID 000517092700263
A CD25+cell suppresses the proliferation of peanut-specific CD8+T cells from nonallergic individuals. Wong, Y., Zhou, X., Nadeau, K. MOSBY-ELSEVIER. 2020: AB89
View details for Web of Science ID 000517092700273
Protein Composition Changes in Manufactured Penaeus aztecus Shrimp Powder Chinthrajah, S., Johansson, J., Woch, M., Conn, T., Chen, E., Long, A., Lyu, S., Kumar, D., Sindher, S., Nadeau, K. MOSBY-ELSEVIER. 2020: AB226
View details for Web of Science ID 000517092700730
Mass Cytometry Reveals Monocytes are Associated with Air Pollution and Blood Pressure in Minority Children Prunicki, M., Nadeau, K., Lee, J., Zhou, X., Movassagh, H., Wu, J. MOSBY-ELSEVIER. 2020: AB128
View details for Web of Science ID 000517092700407
Pollution-Associated Exposure Signature in Teenagers Haddad, F., Cauwenberghs, N., Movassagh, H., Maecker, H., Arthur, J., Wu, J., Nadeau, K., Prunicki, M. MOSBY-ELSEVIER. 2020: AB82
View details for Web of Science ID 000517092700253
Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study Chinthrajah, S., Purington, N., Andorf, S., Long, A., O'Laughlin, K., Lyu, S., Manohar, M., Boyd, S., Tibshirani, R., Maecker, H., Mukai, K., Tsai, M., Desai, M., Galli, S., Nadeau, K. MOSBY-ELSEVIER. 2020: AB181
View details for Web of Science ID 000517092700578
Dose-related Allergic Reactions Decrease Over Time During Peanut Oral Immunotherapy in a Large, Randomized, Double-blind, Placebo-controlled, Phase 2 Study Long, A., Purington, N., Andorf, S., O'Laughlin, K., Lyu, S., Sindher, S., Manohar, M., Boyd, S., Tibshirani, R., Maecker, H., Mukai, K., Tsai, M., Desai, M., Chinthrajah, S., Galli, S., Nadeau, K. MOSBY-ELSEVIER. 2020: AB134
View details for Web of Science ID 000517092700425
Peanut oral immunotherapy induces gastrointestinal eosinophilia in a longitudinal randomized controlled trial Wright, B., Fernandez-Becker, N., Kambham, N., Purington, N., Cao, S., Tupa, D., Zhang, W., Rank, M., Kita, H., Katzka, D., Shim, K., Bunning, B., Doyle, A., Jacobsen, E., Boyd, S., Manohar, M., Galli, S., Nadeau, K., Chinthrajah, S. MOSBY-ELSEVIER. 2020: AB84
View details for Web of Science ID 000517092700258
Th2A and Th17 cell frequencies and regulatory markers as follow-up biomarker candidates for successful multifood oral immunotherapy. Allergy Luce, S., Chinthrajah, S., Lyu, S. C., Nadeau, K., Mascarell, L. 2020
View details for DOI 10.1111/all.14180

View details for PubMedID 31930521
Legends of Allergy: Stephen J. Galli ALLERGY Tsai, M., Chinthrajah, S., Nadeau, K. C. 2020; 75 (1): 243?45
View details for DOI 10.1111/all.13815

View details for Web of Science ID 000506187800034
Remdesivir for the Treatment of Covid-19 - Preliminary Report. The New England journal of medicine Beigel, J. H., Tomashek, K. M., Dodd, L. E., Mehta, A. K., Zingman, B. S., Kalil, A. C., Hohmann, E., Chu, H. Y., Luetkemeyer, A., Kline, S., Lopez de Castilla, D., Finberg, R. W., Dierberg, K., Tapson, V., Hsieh, L., Patterson, T. F., Paredes, R., Sweeney, D. A., Short, W. R., Touloumi, G., Lye, D. C., Ohmagari, N., Oh, M. D., Ruiz-Palacios, G. M., Benfield, T., F�tkenheuer, G., Kortepeter, M. G., Atmar, R. L., Creech, C. B., Lundgren, J., Babiker, A. G., Pett, S., Neaton, J. D., Burgess, T. H., Bonnett, T., Green, M., Makowski, M., Osinusi, A., Nayak, S., Lane, H. C. 2020
Abstract

Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious.We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%).Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number, NCT04280705.).

View details for DOI 10.1056/NEJMoa2007764

View details for PubMedID 32445440

View details for PubMedCentralID PMC7262788
Corrigendum: Analysis of a Large Standardized Food Challenge Data Set to Determine Predictors of Positive Outcome Across Multiple Allergens. Frontiers in immunology Sindher, S., Long, A. J., Purington, N., Chollet, M., Slatkin, S., Andorf, S., Tupa, D., Kumar, D., Woch, M. A., O'Laughlin, K. L., Assaad, A., Pongracic, J., Spergel, J. M., Tam, J., Tilles, S., Wang, J., Galli, S. J., Nadeau, K. C., Chinthrajah, R. S. 2020; 11: 625796
Abstract

[This corrects the article DOI: 10.3389/fimmu.2018.02689.].

View details for DOI 10.3389/fimmu.2020.625796

View details for PubMedID 33329616

View details for PubMedCentralID PMC7734876
Vitamin D insufficiency is associated with reduced regulatory T cell frequency in food-allergic infants. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology Neeland, M. R., Tursi, A. R., Perrett, K. P., Saffery, R., Koplin, J. J., Nadeau, K. C., Andorf, S. 2020
Abstract

The influence of vitamin D on human health is strongly associated with tolerogenic immune function, skewing the immune response toward a regulatory phenotype. Ecological and epidemiological studies have resulted in a proposed link between reduced levels of the most abundant circulating form of vitamin D, 25-hydroxyvitamin D (25(OH)D), and the development of food allergy in children.1 We have also shown that infants with vitamin D insufficiency (? 50nmol/L) were 11 times more likely to have a peanut allergy and 3 times more likely to have an egg allergy relative to infants with sufficient vitamin D levels.2 Interestingly, in the same cohort, 25(OH)D levels positively correlated with tolerogenic immune responses in 4-year-old children who had naturally outgrown their food allergy.3 There is no single accepted mechanism for the proposed association between vitamin D insufficiency and food allergy.4 Rather, a combination of several mechanisms is hypothesized to be involved, including the potential to modulate immune cell proportions or function, including that of regulatory T cells.4.

View details for DOI 10.1111/pai.13439

View details for PubMedID 33351974
Oral Immunotherapy and Basophil and Mast Cell Reactivity in Food Allergy. Frontiers in immunology Paranjape, A., Tsai, M., Mukai, K., Hoh, R. A., Joshi, S. A., Chinthrajah, R. S., Nadeau, K. C., Boyd, S. D., Galli, S. J. 2020; 11: 602660
Abstract

Basophil activation tests (BATs) can closely monitor, in vitro, a patient's propensity to develop type I hypersensitivity reactions. Because of their high specificity and sensitivity, BATs have become promising diagnostic tools, especially in cases with equivocal clinical histories, skin prick test results, and/or levels of specific IgE to allergen extracts. BATs also are useful as tools for monitoring the effects of treatment, since oral immunotherapy (OIT) studies report a diminution in patients' basophil responsiveness over the course of OIT. This review will discuss the BAT findings obtained before, during, and after OIT for food allergy. We will mainly focus on the association of basophil responsiveness, and alterations in basophil surface markers, with clinical outcomes and other clinical features, such as blood levels of specific IgG and IgE antibodies. The detailed analysis of these correlations will ultimately facilitate the use of BATs, along with other blood biomarkers, to differentiate short-term desensitization versus sustained unresponsiveness and to improve treatment protocols. Given the critical anatomic location of mast cells adjacent to the many IgE+ plasma cells found in the gastrointestinal tissues of allergic individuals, we will also discuss the role of gastrointestinal mast cells in manifestations of food allergies.

View details for DOI 10.3389/fimmu.2020.602660

View details for PubMedID 33381123

View details for PubMedCentralID PMC7768812
Homologies between SARS-CoV-2 and allergen proteins may direct T cell-mediated heterologous immune responses. Research square Balz, K., Chen, M., Kaushik, A., Cemic, F., Heger, V., Renz, H., Nadeau, K., Skevaki, C. 2020
Abstract

The outbreak of the new Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a public health emergency. Asthma does not represent a risk factor for COVID-19 in several published cohorts. We hypothesized that the SARS-CoV-2 proteome contains T cell epitopes, which are potentially cross-reactive to allergen epitopes. We aimed at identifying homologous peptide sequences by means of two distinct complementary bioinformatics approaches. Pipeline 1 included prediction of MHC Class I and Class II epitopes contained in the SARS-CoV-2 proteome and allergens along with alignment and elaborate ranking approaches. Pipeline 2 involved alignment of SARS-CoV-2 overlapping peptides with known allergen-derived T cell epitopes. Our results indicate a large number of MHC Class I epitope pairs including known as well as de novo predicted allergen T cell epitopes with high probability for cross-reactivity. Allergen sources, such as Aspergillus fumigatus , Phleum pratense and Dermatophagoides species are of particular interest due to their association with multiple cross-reactive candidate peptides, independently of the applied bioinformatic approach. In contrast, peptides derived from food allergens, as well as MHC class II epitopes did not achieve high in silico ranking and were therefore not further investigated. Our findings warrant further experimental confirmation along with examination of the functional importance of such cross-reactive responses.

View details for DOI 10.21203/rs.3.rs-86873/v1

View details for PubMedID 33052330

View details for PubMedCentralID PMC7553154
Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19 Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19 Kalil, A., Nadeau, K. C., Beigel, J. 2020
Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome. Science immunology R�ltgen, K., Powell, A. E., Wirz, O. F., Stevens, B. A., Hogan, C. A., Najeeb, J., Hunter, M., Wang, H., Sahoo, M. K., Huang, C., Yamamoto, F., Manohar, M., Manalac, J., Otrelo-Cardoso, A. R., Pham, T. D., Rustagi, A., Rogers, A. J., Shah, N. H., Blish, C. A., Cochran, J. R., Jardetzky, T. S., Zehnder, J. L., Wang, T. T., Narasimhan, B., Gombar, S., Tibshirani, R., Nadeau, K. C., Kim, P. S., Pinsky, B. A., Boyd, S. D. 2020; 5 (54)
Abstract

SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, can neutralize the virus. It is, however, unknown which features of the serological response may affect clinical outcomes of COVID-19 patients. We analyzed 983 longitudinal plasma samples from 79 hospitalized COVID-19 patients and 175 SARS-CoV-2-infected outpatients and asymptomatic individuals. Within this cohort, 25 patients died of their illness. Higher ratios of IgG antibodies targeting S1 or RBD domains of spike compared to nucleocapsid antigen were seen in outpatients who had mild illness versus severely ill patients. Plasma antibody increases correlated with decreases in viral RNAemia, but antibody responses in acute illness were insufficient to predict inpatient outcomes. Pseudovirus neutralization assays and a scalable ELISA measuring antibodies blocking RBD-ACE2 interaction were well correlated with patient IgG titers to RBD. Outpatient and asymptomatic individuals' SARS-CoV-2 antibodies, including IgG, progressively decreased during observation up to five months post-infection.

View details for DOI 10.1126/sciimmunol.abe0240

View details for PubMedID 33288645
Epigenetics and the Environment in Airway Disease: Asthma and Allergic Rhinitis. Advances in experimental medicine and biology Long, A., Bunning, B., Sampath, V., DeKruyff, R. H., Nadeau, K. C. 2020; 1253: 153?81
Abstract

Asthma and rhinitis are complex, heterogeneous diseases characterized by chronic inflammation of the upper and lower airways. While genome-wide association studies (GWAS) have identified a number of susceptible loci and candidate genes associated with the pathogenesis of asthma and allergic rhinitis (AR), the risk-associated alleles account for only a very small percent of the genetic risk. In allergic airway and other complex diseases, it is thought that epigenetic modifications, including DNA methylation, histone modifications, and non-coding microRNAs, caused by complex interactions between the underlying genome and the environment may account for some of this "missing heritability" and may explain the high degree of plasticity in immune responses. In this chapter, we will focus on the current knowledge of classical epigenetic modifications, DNA methylation and histone modifications, and their potential role in asthma and AR. In particular, we will review epigenetic variations associated with maternal airway disease, demographics, environment, and non-specific associations. The role of specific genetic haplotypes in environmentally induced epigenetic changes are also discussed. A major limitation of many of the current studies of asthma epigenetics is that they evaluate epigenetic modifications in both allergic and non-allergic asthma, making it difficult to distinguish those epigenetic modifications that mediate allergic asthma from those that mediate non-allergic asthma. Additionally, most DNA methylation studies in asthma use peripheral or cord blood due to poor accessibility of airway cells or tissue. Unlike DNA sequences, epigenetic alterations are quite cell- and tissue-specific, and epigenetic changes found in airway tissue or cells may be discordant from that of circulating blood. These two confounding factors should be considered when reviewing epigenetic studies in allergic airway disease.

View details for DOI 10.1007/978-981-15-3449-2_6

View details for PubMedID 32445095
The importance of the 2S albumins for allergenicity and cross-reactivity of peanuts, tree nuts and sesame seeds. The Journal of allergy and clinical immunology Dreskin, S. C., Koppelman, S., Andorf, S., Nadeau, K. C., Kalra, A., Braun, W., Negi, S. S., Chen, X., Schein, C. H. 2020
Abstract

Allergies to peanuts, tree nuts, and sesame seeds are among the most important food related causes of anaphylaxis. Important clinical questions include: why is there a variable occurrence of co-allergy among these foods and is this immunologically mediated? Clinical and immunological data summarized here suggest an immunologic basis for these co-allergies based on similarities among the 2S-albumins. Data from component resolved diagnostics have highlighted the relationship between IgE binding to these allergens and the presence of IgE-mediated food allergy. Furthermore, in vitro and in vivo experiments provide strong evidence that the 2S albumins are the most important allergens in peanuts for inducing an allergic effector response. Although the 2S albumins are diverse, they have a common disulfide linked core with similar physicochemical properties that make them prime candidates to explain much of the observed co-allergy among peanuts, tree nuts and sesame seeds. The well-established frequency of cashew and pistachio nut co-allergy (64-100%) highlights how the structural similarities among their 2S albumins may account for observed clinical cross-reactivity. A complete understanding of the physicochemical properties of the 2S albumins in peanuts, tree nuts and sesame seeds will enhance our ability to diagnose, treat and ultimately prevent these allergies.

View details for DOI 10.1016/j.jaci.2020.11.004

View details for PubMedID 33217410
Proinflammatory IgG Fc structures in patients with severe COVID-19 Nature Immunology Chakraborty, S., Gonzales, J., Edwards, K., Mallajosyulla, V., Buzzanco, A. S., Sherwood, R., Buffone, C., Kathale, N., Providenza, S., Xie, M. M., Andrews, J. R., Blish, C. A., Singh, U., Dugan, H., Wilson, P. C., Pham, T. D., Boyd, S. D., Nadeau, K. C., Pinsky, B. A., Zhang, S., Memoli, M. J., Taubenberger, J. K., Morales, T., Schapiro, J. M., Tan, G. S., et al 2020
View details for DOI 10.1038/s41590-020-00828-7
Advances and novel developments in environmental influences on the development of atopic diseases. Allergy Alkotob, S. S., Cannedy, C., Harter, K., Movassagh, H., Paudel, B., Prunicki, M., Sampath, V., Schikowski, T., Smith, E., Zhao, Q., Traidl-Hoffmann, C., Nadeau, K. C. 2020
Abstract

Although genetic factors play a role in the etiology of atopic disease, the rapid increases in the prevalence of these diseases over the last few decades suggest that environmental, rather than genetic factors are the driving force behind the increasing prevalence. In modern societies, there is increased time spent indoors, use of antibiotics, and consumption of processed foods and decreased contact with farm animals and pets, which limit exposure to environmental allergens, infectious parasitic worms, and microbes. The lack of exposure to these factors is thought to prevent proper education and training of the immune system. Increased industrialization and urbanization has brought about increases in organic and inorganic pollutants. In addition, Caesarian birth, birth order, increased use of soaps and detergents, tobacco smoke exposure and psychosomatic factors are other factors that have been associated with increased rate of allergic diseases. Here, we review current knowledge on the environmental factors that have been shown to affect the development of allergic diseases and the recent developments in the field.

View details for DOI 10.1111/all.14624

View details for PubMedID 33037680
Oral immunotherapy for peanut allergy: The pro argument. The World Allergy Organization journal Chinthrajah, R. S., Cao, S., Dunham, T., Sampath, V., Chandra, S., Chen, M., Sindher, S., Nadeau, K. 2020; 13 (8): 100455
Abstract

Food allergy (FA) is a growing public health problem with personal, social, nutritional, and economic consequences. In the United States, it is estimated that 8% of children and 10.8% of adults have food allergies. Allergies to peanuts are particularly worrisome as unlike allergies to other allergenic foods, such as milk and egg, which are commonly outgrown by 5 or 10 years of age, 80% of peanut allergies persist into adulthood. The first drug for peanut allergy, Palforzia, was approved by the US Food and Drug Administration (FDA) in January 2020. For other food allergies, the current standard of care for the management of FA is suboptimal and is limited to dietary elimination of the offending allergen, vigilance against accidental ingestion, and treatment of allergic reactions with antihistamines and epinephrine. However, dietary avoidance can be challenging, and it is estimated that approximately 40% of patients with food allergies report at least one food allergy-related emergency department in their lifetime. Reactions, even from minimal exposures, can be life-threatening. Oral immunotherapy (OIT) has been the best researched therapeutic approach for treating FA over the last decade, with clinical trials investigating its efficacy, safety, and ability to improve participants' quality of life (QoL). A number of studies and meta-analyses have shown that OIT treatment is effective in raising the threshold of reactivity to peanuts and other foods in addition to producing a measurable serum immune response to such therapy. Although OIT-related adverse events (AEs) are common during treatment, serious reactions are rare. In fact, while the majority of patients experience AEs related to dosing, most continue daily dosing in hopes of achieving protection against the culprit food. Moreover, the majority of participants report improvement of QoL after OIT and are positive about undergoing OIT. These results show patients' commitment to OIT and their optimism regarding the benefits of treatment. As a first step in therapeutic options to protect from reactions to unintentional ingestion of allergenic foods, and importantly, to address the many psychosocial aspects of living with FA, OIT shows promise. Future research will focus on identifying optimal OIT regimens that maintain protection after therapy and allow for regular food consumption without allergic symptoms. Education and informed shared decision making between patients and providers are essential in optimizing current therapy regimens.

View details for DOI 10.1016/j.waojou.2020.100455

View details for PubMedID 33005286

View details for PubMedCentralID PMC7519204
Human B Cell Clonal Expansion and Convergent Antibody Responses to SARS-CoV-2. Cell host & microbe Nielsen, S. C., Yang, F., Jackson, K. J., Hoh, R. A., R�ltgen, K., Jean, G. H., Stevens, B. A., Lee, J. Y., Rustagi, A., Rogers, A. J., Powell, A. E., Hunter, M., Najeeb, J., Otrelo-Cardoso, A. R., Yost, K. E., Daniel, B., Nadeau, K. C., Chang, H. Y., Satpathy, A. T., Jardetzky, T. S., Kim, P. S., Wang, T. T., Pinsky, B. A., Blish, C. A., Boyd, S. D. 2020
Abstract

B cells are critical for the production of antibodies and protective immunity to viruses. Here we show that patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) display early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. We identify convergence of antibody sequences across SARS-CoV-2-infected patients, highlighting stereotyped naive responses to this virus. Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and SARS-CoV.

View details for DOI 10.1016/j.chom.2020.09.002

View details for PubMedID 32941787
Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy Radzikowska, U., Ding, M., Tan, G., Zhakparov, D., Peng, Y., Wawrzyniak, P., Wang, M., Li, S., Morita, H., Altunbulakli, C., Reiger, M., Neumann, A. U., Lunjani, N., Traidl-Hoffmann, C., Nadeau, K. C., O'Mahony, L., Akdis, C., Sokolowska, M. 2020
Abstract

Morbidity and mortality from COVID-19 caused by novel coronavirus SARS-CoV-2 is accelerating worldwide, and novel clinical presentations of COVID-19 are often reported. The range of human cells and tissues targeted by SARS-CoV-2, its potential receptors and associated regulating factors are still largely unknown. The aim of our study was to analyze the expression of known and potential SARS-CoV-2 receptors and related molecules in the extensive collection of primary human cells and tissues from healthy subjects of different age and from patients with risk factors and known comorbidities of COVID-19.We performed RNA sequencing and explored available RNA-Seq databases to study gene expression and co-expression of ACE2, CD147 (BSG), and CD26 (DPP4) and their direct and indirect molecular partners in primary human bronchial epithelial cells, bronchial and skin biopsies, bronchoalveolar lavage fluid, whole blood, peripheral blood mononuclear cells (PBMCs), monocytes, neutrophils, DCs, NK cells, ILC1, ILC2, ILC3, CD4+ and CD8+ T cells, B cells, and plasmablasts. We analyzed the material from healthy children and adults, and from adults in relation to their disease or COVID-19 risk factor status.ACE2 and TMPRSS2 were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA and PPIB), CD26 (DPP4), and related molecules were expressed in both epithelium and in immune cells. We also observed a distinct age-related expression profile of these genes in the PBMCs and T cells from healthy children and adults. Asthma, COPD, hypertension, smoking, obesity, and male gender status generally led to the higher expression of ACE2- and CD147-related genes in the bronchial biopsy, BAL, or blood. Additionally, CD147-related genes correlated positively with age and BMI. Interestingly, we also observed higher expression of CD147-related genes in the lesional skin of patients with atopic dermatitis.Our data suggest different receptor repertoire potentially involved in the SARS-CoV-2 infection at the epithelial barriers and in the immune cells. Altered expression of these receptors related to age, gender, obesity and smoking, as well as with the disease status, might contribute to COVID-19 morbidity and severity patterns.

View details for DOI 10.1111/all.14429

View details for PubMedID 32496587

View details for PubMedCentralID PMC7300910
Regulation of peanut-specific CD8+ T cells from nonallergic individuals. The Journal of allergy and clinical immunology Yu, W., Zhou, X., Davis, M. M., Nadeau, K. C. 2020
Abstract

Peanut-specific CD8+ T cells in nonallergic individuals are not deleted, but have an expansion block that can be released by impairing regulatory T cell associated signaling pathways.

View details for DOI 10.1016/j.jaci.2020.07.032

View details for PubMedID 32835695
A Notch3-Marked Subpopulation of Vascular Smooth Muscle Cells is the Cell of Origin for Occlusive Pulmonary Vascular Lesions. Circulation Steffes, L. C., Froistad, A. A., Andruska, A., Boehm, M., McGlynn, M., Zhang, F., Zhang, W., Hou, D., Tian, X., Miquerol, L., Nadeau, K., Metzger, R. J., Spiekerkoetter, E., Kumar, M. E. 2020
Abstract

Background: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by profound vascular remodeling in which pulmonary arteries narrow due to medial thickening and occlusion by neointimal lesions, resulting in elevated pulmonary vascular resistance and right heart failure. Therapies targeting the neointima would represent a significant advance in PAH treatment, however our understanding of the cellular events driving neointima formation, and the molecular pathways that control them, remains limited. Methods: We comprehensively map the stepwise remodeling of pulmonary arteries in a robust, chronic inflammatory mouse model of pulmonary hypertension. This model demonstrates pathologic features of the human disease, including increased right ventricular pressures, medial thickening, neointimal lesion formation, elastin breakdown, increased anastomosis within the bronchial circulation, and perivascular inflammation. Using genetic lineage tracing, clonal analysis, multiplexed in situ hybridization, immunostaining, deep confocal imaging and staged pharmacologic inhibition we define the cell behaviors underlying each stage of vascular remodeling and identify a pathway required for neointima formation. Results: Neointima arises from smooth muscle cells (SMCs) and not endothelium. Medial SMCs proliferate broadly to thicken the media, after which a small number of SMCs are selected to establish the neointima. These neointimal founder cells subsequently undergoing massive clonal expansion to form occlusive neointimal lesions. The normal pulmonary artery SMC population is heterogeneous and we identify a Notch3-marked minority subset of SMCs as the major neointimal cell of origin. Notch signaling is specifically required for the selection of neointimal founder cells, and Notch inhibition significantly improves pulmonary artery pressure in animals with pulmonary hypertension. Conclusions: This work describes the first nongenetically driven murine model of PH that generates robust and diffuse occlusive neointimal lesions across the pulmonary vascular bed and does so in a stereotyped timeframe. We uncover distinct cellular and molecular mechanisms underlying medial thickening and neointima formation and highlight novel transcriptional, behavioral and pathogenic heterogeneity within pulmonary artery SMCs. In this model, inflammation is sufficient to generate characteristic vascular pathologies and physiologic measures of human PAH. We hope that identifying the molecular cues regulating each stage of vascular remodeling will open new avenues for therapeutic advancements in the treatment of PAH.

View details for DOI 10.1161/CIRCULATIONAHA.120.045750

View details for PubMedID 32794408
Increased diversity of gut microbiota during active oral immunotherapy in peanut allergic adults. Allergy He, Z., Vadali, V. G., Szabady, R. L., Zhang, W., Norman, J. M., Roberts, B., Tibshirani, R., Desai, M., Chinthrajah, R. S., Galli, S. J., Andorf, S., Nadeau, K. C. 2020
View details for DOI 10.1111/all.14540

View details for PubMedID 32750160
The Origins of Allergy from a Systems Approach. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology Krempski, J. W., Dant, C., Nadeau, K. C. 2020
Abstract

The origin of allergic disease has traditionally been explained by IgEmediated immune responses to account for asthma, atopic dermatitis, atopic rhinitis, and food allergy. Research insights into disease origins support broader array of factors that predispose, initiate, or exacerbate altered immunity in allergic diseases: inherent epithelial barrier dysfunction, loss of immune tolerance, disturbances in gut and organ-specific microbiomes, diet, and age. Here, we discuss these influences that together form a better understanding of allergy as a systems disease.We summarize recent advances in epithelial dysfunction, environmental influences, inflammation, infection, alterations in specific microbiome, and inherent genetic predisposition.We performed a literature search targeting primary and review articles.We explored microbial-epithelial-immune interactions underlying the early-life origins of allergic disorders, and examined immune mechanisms suggesting novel disease prevention or intervention strategies. Damage to epithelial surfaces lies at the origin of various manifestations of allergic disease. As a sensor of environmental stimuli, the epithelium of the lungs, gut, and skin is impacted by an altered microbiome, air pollution, food allergens in a changed diet, and chemicals in modern detergents. This collectively leads to alterations of lung, skin, or gut epithelial surfaces, driving a type-2 immune response that underlies atopic diseases. Treatment and prevention of allergic diseases include biologics, oral desensitization, targeted gut microbiome alterations, and changes in behavior.Understanding the spectrum of allergy as a systems disease will allow us to better define the mechanisms of allergic disorders and improve their treatment.

View details for DOI 10.1016/j.anai.2020.07.013

View details for PubMedID 32702411
Immunology of COVID-19: mechanisms, clinical outcome, diagnostics and perspectives - a report of the European Academy of Allergy and Clinical Immunology (EAACI). Allergy Sokolowska, M., Lukasik, Z., Agache, I., Akdis, C. A., Akdis, D., Akdis, M., Barcik, W., Brough, H., Eiwegger, T., Eliaszewicz, A., Eyerich, S., Feleszko, W., Gomez Casado, C., Hoffmann-Sommergruber, K., Janda, J., Jim�nez-Saiz, R., Jutel, M., Knol, E., Kortekaas Krohn, I., Kothari, A., Makowska, J., Moniuszko, M., Morita, H., O'Mahony, L., Nadeau, K., Ozdemir, C., Pali-Sch�ll, I., Palomares, O., Papaleo, F., Prunicki, M., Schmidt-Weber, C. B., Sediva, A., Schwarze, J., Shamji, M. H., Tramper-Stranders, G., van, W., Untersmayr, E. 2020
Abstract

With the worldwide spread of the novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) resulting in declaration of a pandemic by the World Health Organization (WHO) on March 11, 2020, the SARS-CoV-2-induced Coronavirus disease-19 (COVID-19) has become one of the main challenges of our times. The high infection rate and the severe disease course led to major safety and social restriction measures worldwide. There is an urgent need of unbiased expert knowledge guiding the development of efficient treatment and prevention strategies. This report summarizes current immunological data on mechanisms associated with the SARS-CoV-2 infection and COVID-19 development and progression to the most severe forms. We characterize the differences between adequate innate and adaptive immune response in mild disease and the deep immune dysfunction in the severe multi-organ disease. The similarities of the human immune response to SARS-CoV-2 and the SARS-CoV and MERS-CoV are underlined. We also summarize known and potential SARS-CoV-2 receptors on epithelial barriers, immune cells, endothelium and clinically involved organs such as lung, gut, kidney, cardiovascular and neuronal system. Finally, we discuss the known and potential mechanisms underlying the involvement of comorbidities, gender and age in development of COVID-19. Consequently, we highlight the knowledge gaps and urgent research requirements to provide a quick roadmap for ongoing and needed COVID-19 studies.

View details for DOI 10.1111/all.14462

View details for PubMedID 32584441
Barriers to Food Allergy Management Among Low-Income Americans. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology Bozen, A., Zaslavsky, J. M., Cohn, D., Samady, W., Lombard, L., Nadeau, K., Tobin, M., Warren, C. M., Gupta, R. S. 2020
View details for DOI 10.1016/j.anai.2020.05.007

View details for PubMedID 32437837
Epicutaneous sensitization in the development of food allergy: What is the evidence and how can this be prevented? Allergy Brough, H. A., Nadeau, K. C., Sindher, S. B., Alkotob, S. S., Chan, S., Bahnson, H., Leung, D. Y., Lack, G. 2020
Abstract

There is increasing evidence regarding the importance of allergic sensitization through the skin. In this review, we provide an overview of the atopic march and immune mechanism underlying the sensitization and effector phase of food allergy. We present experimental models and human data that support the concept of epicutaneous sensitization and how this forms one half of the dual-allergen exposure hypothesis. We discuss specific important elements in the skin (FLG and other skin barrier gene mutations, Langerhans cells, type 2 innate lymphoid cells, IL-33, TSLP) that have important roles in the development of allergic responses as well as the body of evidence on environmental allergen exposure and how this can sensitize an individual. Given the link between skin barrier impairment, atopic dermatitis, food allergy, allergic asthma, and allergic rhinitis, it is logical that restoring the skin barrier and prevention or treating atopic dermatitis would have beneficial effects on prevention of related allergic diseases, particularly food allergy. We present the experimental and human studies that have evaluated this approach and discuss various factors which may influence the success of these approaches, such as the type of emollient chosen for the intervention, the role of managing skin inflammation, and differences between primary and secondary prevention of atopic dermatitis to achieve the desired outcome.

View details for DOI 10.1111/all.14304

View details for PubMedID 32249942
A highly sensitive bioluminescent method for measuring allergen-specific IgE in microliter samples. Allergy Goyard, S., Balbino, B., Chinthrajah, R. S., Lyu, S. C., Janin, Y. L., Bruhns, P., Poncet, P., Galli, S. J., Nadeau, K. C., Reber, L. L., Rose, T. 2020
View details for DOI 10.1111/all.14365

View details for PubMedID 32407549
Microfluidic methods for precision diagnostics in food allergy. Biomicrofluidics Casta�o, N., Cordts, S. C., Nadeau, K. C., Tsai, M., Galli, S. J., Tang, S. K. 2020; 14 (2): 021503
Abstract

Food allergy has reached epidemic proportions and has become a significant source of healthcare burden. Oral food challenge, the gold standard for food allergy assessment, often is not performed because it places the patient at risk of developing anaphylaxis. However, conventional alternative food allergy tests lack a sufficient predictive value. Therefore, there is a critical need for better diagnostic tests that are both accurate and safe. Microfluidic methods have the potential of helping one to address such needs and to personalize the diagnostics. This article first reviews conventional diagnostic approaches used in food allergy. Second, it reviews recent efforts to develop novel biomarkers and in vitro diagnostics. Third, it summarizes the microfluidic methods developed thus far for food allergy diagnosis. The article concludes with a discussion of future opportunities for using microfluidic methods for achieving precision diagnostics in food allergy, including multiplexing the detection of multiple biomarkers, sampling of tissue-resident cytokines and immune cells, and multi-organ-on-a-chip technology.

View details for DOI 10.1063/1.5144135

View details for PubMedID 32266046

View details for PubMedCentralID PMC7127910
Cumulative Lifetime Burden of Cardiovascular Disease From Early Exposure to Air Pollution. Journal of the American Heart Association Kim, J. B., Prunicki, M., Haddad, F., Dant, C., Sampath, V., Patel, R., Smith, E., Akdis, C., Balmes, J., Snyder, M. P., Wu, J. C., Nadeau, K. C. 2020; 9 (6): e014944
Abstract

The disease burden associated with air pollution continues to grow. The World Health Organization (WHO) estimates ?7�million people worldwide die yearly from exposure to polluted air, half of which-3.3�million-are attributable to cardiovascular disease (CVD), greater than from major modifiable CVD risks including smoking, hypertension, hyperlipidemia, and diabetes mellitus. This serious and growing health threat is attributed to increasing urbanization of the world's populations with consequent exposure to polluted air. Especially vulnerable are the elderly, patients with pre-existing CVD, and children. The cumulative lifetime burden in children is particularly of concern because their rapidly developing cardiopulmonary systems are more susceptible to damage and they spend more time outdoors and therefore inhale more pollutants. World Health Organization estimates that 93% of the world's children aged <15�years-1.8�billion children-breathe air that puts their health and development at risk. Here, we present growing scientific evidence, including from our own group, that chronic exposure to air pollution early in life is directly linked to development of major CVD risks, including obesity, hypertension, and metabolic disorders. In this review, we surveyed the literature for current knowledge of how pollution exposure early in life adversely impacts cardiovascular phenotypes, and lay the foundation for early intervention and other strategies that can help prevent this damage. We also discuss the need for better guidelines and additional research to validate exposure metrics and interventions that will ultimately help healthcare providers reduce the growing burden of CVD from pollution.

View details for DOI 10.1161/JAHA.119.014944

View details for PubMedID 32174249
Origins and clonal convergence of gastrointestinal IgE+ B cells in human peanut allergy. Science immunology Hoh, R. A., Joshi, S. A., Lee, J. Y., Martin, B. A., Varma, S., Kwok, S., Nielsen, S. C., Nejad, P., Haraguchi, E., Dixit, P. S., Shutthanandan, S. V., Roskin, K. M., Zhang, W., Tupa, D., Bunning, B. J., Manohar, M., Tibshirani, R., Fernandez-Becker, N. Q., Kambham, N., West, R. B., Hamilton, R. G., Tsai, M., Galli, S. J., Chinthrajah, R. S., Nadeau, K. C., Boyd, S. D. 2020; 5 (45)
Abstract

B cells in human food allergy have been studied predominantly in the blood. Little is known about IgE+ B cells or plasma cells in tissues exposed to dietary antigens. We characterized IgE+ clones in blood, stomach, duodenum, and esophagus of 19 peanut-allergic patients, using high-throughput DNA sequencing. IgE+ cells in allergic patients are enriched in stomach and duodenum, and have a plasma cell phenotype. Clonally related IgE+ and non-IgE-expressing cell frequencies in tissues suggest local isotype switching, including transitions between IgA and IgE isotypes. Highly similar antibody sequences specific for peanut allergen Ara h 2 are shared between patients, indicating that common immunoglobulin genetic rearrangements may contribute to pathogenesis. These data define the gastrointestinal tract as a reservoir of IgE+ B lineage cells in food allergy.

View details for DOI 10.1126/sciimmunol.aay4209

View details for PubMedID 32139586
Immunologic effects of forest fire exposure show increases in IL-1? and CRP. Allergy Prunicki, M. M., Dant, C. C., Cao, S., Maecker, H., Haddad, F., Kim, J. B., Snyder, M., Wu, J., Nadeau, K. 2020
View details for DOI 10.1111/all.14251

View details for PubMedID 32112439
Mass cytometry reveals cellular fingerprint associated with IgE+?peanut tolerance and allergy in early life. Nature communications Neeland, M. R., Andorf, S., Manohar, M., Dunham, D., Lyu, S. C., Dang, T. D., Peters, R. L., Perrett, K. P., Tang, M. L., Saffery, R., Koplin, J. J., Nadeau, K. C. 2020; 11 (1): 1091
Abstract

IgE-mediated peanut allergic is common, often serious, and usually lifelong. Not all individuals who produce peanut-specific IgE will react upon consumption of peanut and can eat the food without adverse reactions, known as sensitized tolerance. Here, we employ high-dimensional mass cytometry to define the circulating immune cell signatures associated with sensitized tolerance and clinical allergy to peanut in the first year of life. Key features of clinical peanut allergic are increased frequency of activated B cells (CD19hiHLADRhi), overproduction of TNF? and increased frequency of peanut-specific memory CD4 T cells. Infants with sensitized tolerance display reduced frequency but hyper-responsive naive CD4 T cells and an increased frequency of plasmacytoid dendritic cells. This work demonstrates the utility and power of high-dimensional mass cytometry analysis to interrogate the cellular interactions that are associated with allergic sensitization and clinical food allergy in the first year of life.

View details for DOI 10.1038/s41467-020-14919-4

View details for PubMedID 32107388
Enhancing Data Reliability in TOMAHAQ for Large-Scale Protein Quantification. Proteomics Liu, F., Singhal, K., Matney, R., Acharya, S., Akdis, C. A., Nadeau, K. C., Chien, A. S., Leib, R. D. 2020: e1900105
Abstract

The analytical scale of most mass spectrometry (MS)-based targeted proteomics assays is usually limited by assay performance and instrument utilization. A recently introduced method, called Triggered by Offset, Multiplexed, Accurate mass, High resolution, and Absolute Quantitation (TOMAHAQ), combines both peptide and sample multiplexing to simultaneously improve analytical scale and quantitative performance. In the present work we discuss critical technical requirements and data analysis considerations for successful implementation of the TOMAHAQ technique based on our study of a total of 185 target peptides across over 200 clinical plasma samples. Importantly, we observed significant interference originating from the TMTzero reporter ion used for the synthetic trigger peptides. This interference is not expected because only TMT10plex reporter ions from the target peptides should be observed under typical TOMAHAQ conditions. In order to unlock the great promise of the technique for high throughput quantification, here we propose a post-acquisition data correction strategy to deconvolute the reporter ion superposition and recover reliable data. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/pmic.201900105

View details for PubMedID 32032464
The future of omics for clinical practice ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY Long, A., Bunning, B., Borro, M., Sampath, V., Nadeau, K. C. 2019; 123 (6): 535?36
View details for DOI 10.1016/j.anai.2019.07.016

View details for Web of Science ID 000498692800004

View details for PubMedID 31351978
Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care ALLERGY Breiteneder, H., Diamant, Z., Eiwegger, T., Fokkens, W. J., Traidl-Hoffmann, C., Nadeau, K., O'Hehir, R. E., O'Mahony, L., Pfaar, O., Torres, M. J., Wang, D., Zhang, L., Akdis, C. A. 2019; 74 (12): 2293?2311
Abstract

The specialties of allergy and clinical immunology have entered the era of precision medicine with the stratification of diseases into distinct disease subsets, specific diagnoses, and targeted treatment options, including biologicals and small molecules. This article reviews recent developments in research and patient care and future trends in the discipline. The section on basic mechanisms of allergic diseases summarizes the current status and defines research needs in structural biology, type 2 inflammation, immune tolerance, neuroimmune mechanisms, role of the microbiome and diet, environmental factors, and respiratory viral infections. In the section on�diagnostic challenges, clinical trials, precision medicine and immune monitoring of allergic diseases, asthma, allergic and nonallergic rhinitis, and new approaches to the diagnosis and treatment of drug hypersensitivity reactions are discussed in further detail. In the third section, unmet needs and future research areas for the treatment of allergic diseases are highlighted with topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen-specific immunotherapy for airway disease. Unknowns and future research needs are discussed at the end of each subsection.

View details for DOI 10.1111/all.13851

View details for Web of Science ID 000517148400002

View details for PubMedID 31056763

View details for PubMedCentralID PMC6973012
Cow's Milk and Vitamin D Supplementation in Infants-Timing Is Everything JAMA PEDIATRICS du Toit, G., Elizur, A., Nadeau, K. C. 2019; 173 (12): 1129?30
View details for DOI 10.1001/jamapediatrics.2019.3560

View details for Web of Science ID 000505183100004

View details for PubMedID 31633773
Transcriptomic and methylomic features in asthmatic and non-asthmatic twins. Allergy Dhondalay, G. K., Bunning, B., Bauer, R. N., Barnathan, E. S., Maniscalco, C., Baribaud, F., Nadeau, K. C., Andorf, S. 2019
View details for DOI 10.1111/all.14128

View details for PubMedID 31758558
Trends in egg specific immunoglobulin levels during natural tolerance and oral immunotherapy. Allergy Andorf, S., Bunning, B., Tupa, D., Cao, S., Long, A. J., Borres, M. P., Galli, S. J., Chinthrajah, R. S., Nadeau, K. C. 2019
View details for DOI 10.1111/all.14107

View details for PubMedID 31724180
Phase 2a randomized, placebo-controlled study of anti-IL-33 in peanut allergy. JCI insight Chinthrajah, S., Cao, S., Liu, C., Lyu, S., Sindher, S. B., Long, A., Sampath, V., Petroni, D., Londei, M., Nadeau, K. C. 2019; 4 (22)
Abstract

BACKGROUNDIL-33, found in high levels in participants with allergic disorders, is thought to mediate allergic reactions. Etokimab, an anti-IL-33 biologic, has previously demonstrated a good safety profile and favorable pharmacodynamic properties in many clinical studies.METHODSIn this 6-week placebo-controlled phase 2a study, we evaluated the safety and the ability of a single dose of etokimab to desensitize peanut-allergic adults. Participants received either etokimab (n = 15) or blinded placebo (n = 5). Clinical tests included oral food challenges and skin prick tests at days 15 and 45. Blood samples were collected for IgE levels and measurement of ex vivo peanut-stimulated T cell cytokine production.RESULTSEfficacy measurements for active vs. placebo participants at the day 15 and 45 food challenge (tolerating a cumulative 275 mg of peanut protein, which was the food challenge outcome defined in this paper) demonstrated, respectively, 73% vs. 0% (P = 0.008) to 57% vs. 0% (ns). The etokimab group had fewer adverse events compared with placebo. IL-4, IL-5, IL-9, IL-13, and ST2 levels in CD4+ T cells were reduced in the active vs. placebo arm upon peanut-induced T cell activation (P = 0.036 for IL-13 and IL-9 at day 15), and peanut-specific IgE was reduced in active vs. placebo (P = 0.014 at day 15).CONCLUSIONThe phase 2a results suggest etokimab is safe and well tolerated and that a single dose of etokimab could have the potential to desensitize peanut-allergic participants and possibly reduce atopy-related adverse events.TRIAL REGISTRATIONClinicalTrials.gov NCT02920021.FUNDINGThis work was supported by NIH grant R01AI140134, AnaptysBio, the Hartman Vaccine Fund, and the Sean N. Parker Center for Allergy and Asthma Research at Stanford University.

View details for DOI 10.1172/jci.insight.131347

View details for PubMedID 31723064
Genetic and environmental susceptibility to food allergy in a registry of twins JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE Kivisto, J. E., Clarke, A., Dery, A., De Schryver, S., Shand, G., Huhtala, H., Makela, M. J., Asai, Y., Nadeau, K., Harada, L., Chan, E. S., Ben-Shoshan, M. 2019; 7 (8): 2916?18
View details for DOI 10.1016/j.jaip.2019.05.016

View details for Web of Science ID 000495746100070

View details for PubMedID 31129075
Conflicting verdicts on peanut OIT from the ICER and FDA Advisory Committee; where do we go from here? The Journal of allergy and clinical immunology Eiwegger, T., Anagnostou, K., Arasi, S., Begin, P., Ben-Shoshan, M., Beyer, K., Blumchen, K., Brough, H., Caubet, J., Chan, E. S., Chen, M., Chinthrajah, S., Davis, C. M., Roches, A. D., Du Toit, G., Elizur, A., Galli, S. J., Haland, G., Hoffmann-Sommergruber, K., Kim, H., Leung, D. Y., Long, A., Muraro, A., Nurmatov, U. B., Pajno, G. B., Sampath, V., Saxena, J., Sindher, S., Upton, J., Worm, M., Nadeau, K. 2019
View details for DOI 10.1016/j.jaci.2019.10.021

View details for PubMedID 31678426
The impact of prescribed fire versus wildfire on the immune and cardiovascular systems of children ALLERGY Prunicki, M., Kelsey, R., Lee, J., Zhou, X., Smith, E., Haddad, F., Wu, J., Nadeau, K. 2019; 74 (10): 1989?91
View details for DOI 10.1111/all.13825

View details for Web of Science ID 000493013400015
Innovative pediatric clinical outcome assessment (COA) administration and reporting strategies Turner-Bowker, D., Loftus, J., Yaworsky, A., Krohe, M., Radin, A., Palladino, A., Mastey, V., Nadeau, K., Kelly, M., Lamoureux, R., Padilla, B., Love, E., Chaston, E., Jalbert, J. SPRINGER. 2019: S9
View details for Web of Science ID 000486499800022
Pru du 8: First member of a new food allergen family Zhang, Y., Che, H., Jiang, S., Jin, T., Lyu, S., Nadeau, K., McHugh, T. AMER CHEMICAL SOC. 2019
View details for Web of Science ID 000525055500367
Almond (Prunus dulcis) Allergen Pru du 8, the First Member of a New Family of Food Allergens JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY Che, H., Zhang, Y., Jiang, S., Jin, T., Lyu, S., Nadeau, K. C., McHugh, T. 2019; 67 (31): 8626?31
Abstract

An almond allergen with two known short peptide sequences was reported as the almond 2S albumin but was later suspected to be almond vicilin. However, this allergen was not designated by the World Health Organization/International Union of Immunological Societies. This study aimed to determine the true identity of this elusive almond allergen. cDNAs were synthesized from total RNA of the Nonpareil almond. The complete sequence of the previously reported almond allergen was determined from its coding sequence. The deduced protein was produced recombinantly and was confirmed to be a food allergen by testing with 18 almond-allergic sera. The allergen is a potential cysteine-rich antimicrobial protein with characteristic C[X]3C-[X]10-12-C[X]3C motifs of the hairpinin antimicrobial protein. This first member of a novel family of food allergens was named Pru du 8. The signature motif of the hairpinin antimicrobial protein can be found in the N-terminal region of some vicilin allergens (e.g., Ara h 1). It can also be found in the signal peptide of other vicilin allergens (e.g., Car i 2). In many species, however, vicilins do not contain such a motif, indicating that the presence of the signature motifs of the hairpinin antimicrobial protein in vicilins might be a result of translocation during evolution.

View details for DOI 10.1021/acs.jafc.9b02781

View details for Web of Science ID 000480498000023

View details for PubMedID 31287307
Allergen-specific CD8(+) T cells in peanut-allergic individuals JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Yu, W., Zhou, X., Dunham, D., Lyu, S., Manohar, M., Zhang, W., Zhao, F., Davis, M. M., Nadeau, K. 2019; 143 (5): 1948?52
View details for DOI 10.1016/j.jaci.2019.01.011

View details for Web of Science ID 000466784600036
Laundry detergents and detergent residue after rinsing directly disrupt tight junction barrier integrity in human bronchial epithelial cells JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Wang, M., Tan, G., Eljaszewicz, A., Meng, Y., Wawrzyniak, P., Acharya, S., Altunbulakli, C., Westermann, P., Dreher, A., Yan, L., Wang, C., Akdis, M., Zhang, L., Nadeau, K. C., Akdis, C. A. 2019; 143 (5): 1892?1903
View details for DOI 10.1016/j.jaci.2018.11.016

View details for Web of Science ID 000466784600024
Combined immune and airway epithelial cell profiles define asthma severity phenotypes Oriss, T. B., Zhou, X., Camiolo, M., Scholl, K. L., Gorry, M., Gauthier, M., Ray, P., Wenzel, S. E., Nadeau, K., Ray, A. AMER ASSOC IMMUNOLOGISTS. 2019
View details for Web of Science ID 000524982500462
Changing Patient Mindsets about Non-Life-Threatening Symptoms During Oral Immunotherapy: A Randomized Clinical Trial JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE Howe, L. C., Leibowitz, K. A., Perry, M. A., Bitler, J. M., Block, W., Kaptchuk, T. J., Nadeau, K. C., Crum, A. J. 2019; 7 (5): 1550?59
View details for DOI 10.1016/j.jaip.2019.01.022

View details for Web of Science ID 000467072700022
Mind the gaps: Clinical trial concepts to address unanswered questions in aeroallergen immunotherapy-An NIAID/AHRQ Workshop JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Wheatley, L. M., Wood, R., Nadeau, K., Liu, A., Zoratti, E., Bacharier, L., Brittain, E., Calderon, M., Casale, T., Chipps, B., Cox, L., Creticos, P. S., Desai, M., Dreborg, S., Durham, S., Gergen, P. J., Gruchalla, R., Nelson, H., O'Hehir, R. E., Plaut, M., Schwaninger, J. M., Tilles, S., Vickery, B., Wittenberg, K. M., Togias, A. 2019; 143 (5): 1711?26
View details for DOI 10.1016/j.jaci.2019.01.032

View details for Web of Science ID 000466784600005
The Impact of Prescribed Fire versus Wildfire on the Immune and Cardiovascular Systems of Children. Allergy Prunicki, M., Kelsey, R., Lee, J., Zhou, X., Smith, E., Haddad, F., Wu, J., Nadeau, K. 2019
View details for PubMedID 31002401
Legends of Allergy: Stephen J. Galli. Allergy Tsai, M., Chinthrajah, S., Nadeau, K. C. 2019
Abstract

Professor Stephen J. Galli's rigorous and innovative research in the field of allergy and immunology has truly made him a legend in the field. His accomplishments are many as are the awards and recognitions he has received. He and his team have published approximately 430 peer-reviewed publications and 14 patents. He has chaired, organized, or co-organized 16 scientific meetings or symposia. Some of the major awards he has received are the MERIT award from NIAID/NIH (1995), Scientific Achievement Award from the International Association of Allergy and Clinical Immunology (1997), Scientific Achievement Award from the World Allergy Organization (2011), Rous-Whipple Award of the American Society for Investigative Pathology (2014), and the Karl Landsteiner Medal of the Austrian Society of Allergology and Immunology (2014). This article is protected by copyright. All rights reserved.

View details for PubMedID 30964544
Newly identified T cell subsets in mechanistic studies of food immunotherapy JOURNAL OF CLINICAL INVESTIGATION Sampath, V., Nadeau, K. C. 2019; 129 (4): 1431?40
View details for DOI 10.1172/JCI024605

View details for Web of Science ID 000464278200005
Newly identified T cell subsets in mechanistic studies of food immunotherapy. The Journal of clinical investigation Sampath, V., Nadeau, K. C. 2019; 129 (4): 1431?40
Abstract

Allergen-specific immunotherapy has shown promise for the treatment of food allergy and is currently being evaluated in clinical trials. Although immunotherapy can induce desensitization, the mechanisms underlying this process are not completely understood. Recent advances in high-throughput technologies along with concomitant advances in data analytics have enabled monitoring of cells at the single-cell level and increased the research focus on upstream cellular factors involved in the efficacy of immunotherapy, particularly the role of T cells. As our appreciation of different T cell subsets and their plasticity increases, the initial simplistic view that restoring Th1/Th2 balance by decreasing Th2 or increasing Th1 responses can ameliorate food allergy is being enhanced by a more complex model involving other T cell subsets, particularly Tregs. In this Review, we focus on the current understanding of T cell functions in food allergy, tolerance, and immunotherapy.

View details for DOI 10.1172/JCI124605

View details for PubMedID 30932909
A perspective on the pediatric death from oral food challenge reported from the Allergy Vigilance Network. Allergy Upton, J., Alvaro, M., Nadeau, K. 2019
Abstract

The current edition of Allergy contains a report of 18 food allergy deaths from the French Anaphylaxis Vigilance Network (AVN) from 2002-20181 . The AVN maintains a database of food allergy related severe anaphylaxis formed of voluntary, structured reports of anonymous patients submitted by allergists. Therefore, no population estimates can be made, but important cases can be revealed. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/all.13791

View details for PubMedID 30893474
Predicting development of sustained unresponsiveness to milk oral immunotherapy using epitope-specific antibody binding profiles JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Suarez-Farinas, M., Suprun, M., Chang, H. L., Gimenez, G., Grishina, G., Getts, R., Nadeau, K., Wood, R. A., Sampson, H. A. 2019; 143 (3): 1038?46
View details for DOI 10.1016/j.jaci.2018.10.028

View details for Web of Science ID 000460272900024
Mind the gaps: clinical trial concepts to address unanswered questions in aeroallergen immunotherapy. An NIAID/AHRQ Workshop. The Journal of allergy and clinical immunology Wheatley, L. M., Wood, R., Nadeau, K., Liu, A., Zoratti, E., Bacharier, L., Brittain, E., Calderon, M., Casale, T., Chipps, B., Cox, L., Creticos, P. S., Desai, M., Dreborg, S., Durham, S., Gergen, P. J., Gruchalla, R., Nelson, H., O'Hehir, R. E., Plaut, M., Schwaninger, J. M., Tilles, S., Vickery, B., Wittenberg, K. M., Togias, A. 2019
Abstract

The Agency for Healthcare Research and Quality and the National Institute of Allergy and Infectious Diseases organized a workshop to develop trial concepts that could improve the usage and effectiveness of aeroallergen immunotherapy (AAIT). Expert groups were formed to accomplish the following tasks: 1) Propose a study design to compare effectiveness and safety of subcutaneous versus sublingual AAIT; 2) Propose a study design to compare effectiveness and safety of AAIT using one or a few allergens vs all or most allergens to which a patient is sensitized; 3) Propose a study design to determine whether AAIT can alter the progression of childhood allergic airways disease; 4) Propose a study design to determine the optimal dose and duration of AAIT to achieve maximal effectiveness with acceptable safety. Study designs were presented by the workgroups, extensively discussed at the workshop and revised for this report. The proposed trials would be of long duration, and require large, highly characterized patient populations. Scientific caveats and feasibility matters are discussed. These concepts are intended to help the development of clinical trials that can address some of the major questions related to the practice of AAIT for the management and prevention of allergic airways disease.

View details for PubMedID 30731123
Esophageal Eosinophilia is Present in Some Peanut Allergic Patients Fernandez-Becker, N., Wright, B. L., Kambham, N., Shim, K. P., Purington, N., Long, A. J., Tsai, M., Boyd, S., Galli, S. J., Nadeau, K. C., Chinthrajah, R. MOSBY-ELSEVIER. 2019: AB310
View details for DOI 10.1016/j.jaci.2018.12.942

View details for Web of Science ID 000457771200928
Multi-Omic Profiling Of Asthma Using High-Throughput Sequencing Dhondalay, G., Bunning, B. J., Nadeau, K. C., Andorf, S. MOSBY-ELSEVIER. 2019: AB203
View details for DOI 10.1016/j.jaci.2018.12.621

View details for Web of Science ID 000457771200612
Component IgE and IgG4 levels in patients with natural tolerance or oral immunotherapy treatment Bunning, B. J., Long, A. J., Chinthrajah, R., Nadeau, K. C., Andorf, S. MOSBY-ELSEVIER. 2019: AB246
View details for DOI 10.1016/j.jaci.2018.12.753

View details for Web of Science ID 000457771200741
Association Between History of Epinephrine Use and Dose-Related Adverse Event Rates During Oral Immunotherapy Scheiber, A., Chinthrajah, R., Long, A. J., Kumar, D., Skura, S., Shojinaga, M., Min, H., Alvarez, A., Lloret, M., Nadeau, K. C., Sindher, S. B. MOSBY-ELSEVIER. 2019: AB247
View details for DOI 10.1016/j.jaci.2018.12.756

View details for Web of Science ID 000457771200744
Effectiveness Of Clinician Dose Blinding In An Oral Immunotherapy Protocol Woch, M., O'Laughlin, K., Tan, T., Long, A. J., Bunning, B. J., Kumar, D., Chinthrajah, R., Nadeau, K. C. MOSBY-ELSEVIER. 2019: AB73
View details for Web of Science ID 000457771200219
Alternative dosing of omalizumab as an adjunct therapy during multiallergen oral immunotherapy in food allergic patients Sindher, S. B., Long, A. J., Purington, N., Kumar, D., Scheiber, A., O'Laughlin, K., Woch, M., Tan, T., Chinthrajah, R., Zedeck, S., Lloret, M., Nadeau, K. C. MOSBY-ELSEVIER. 2019: AB245
View details for DOI 10.1016/j.jaci.2018.12.749

View details for Web of Science ID 000457771200737
Identification of Almond (Prunus dulcis) Vicilin as a Food Allergen Zhang, Y., Che, H., Lyu, S., Nadeau, K. C., McHugh, T. MOSBY-ELSEVIER. 2019: AB70
View details for Web of Science ID 000457771200208
Epicutaneous Immunotherapy (EPIT) for Peanut Allergy in Young Children Fleischer, D. M., Brown-Whitehorn, T. F., Jones, S. M., Kim, E., Nadeau, K. C., Wang, J., Wood, R. A., Nowak-Wegrzyn, A. H., Jaffrelot, A., Green, T., Burks, A. MOSBY-ELSEVIER. 2019: AB247
View details for DOI 10.1016/j.jaci.2018.12.754

View details for Web of Science ID 000457771200742
The Impact of a Prescribed Burn versus a Wildfire on the Immune and Cardiovascular Systems of Children Prunicki, M., Zhou, X., Nadeau, K. MOSBY-ELSEVIER. 2019: AB81
View details for Web of Science ID 000457771200248
Immune Mechanism of Desensitization through Rapid Multi-food Oral Immunotherapy Manohar, M., Andorf, S., Gupta, S., Dunham, D., Zhang, W., Maecker, H. T., Galli, S. J., Chinthrajah, R., Nadeau, K. C. MOSBY-ELSEVIER. 2019: AB254
View details for DOI 10.1016/j.jaci.2018.12.775

View details for Web of Science ID 000457771200763
Desensitization rates to peanut protein during OIT among children, adolescents, and adults Long, A. J., Purington, N., Woch, M., O'Laughlin, K., Tan, T., Kost, L., Hijazi, S., Shojinaga, M., Raeber, O., Alvarez, A., Andorf, S., Tibshirani, R., Galli, S. J., Nadeau, K. C., Chinthrajah, R. MOSBY-ELSEVIER. 2019: AB245
View details for DOI 10.1016/j.jaci.2018.12.750

View details for Web of Science ID 000457771200738
Allergen Specific CD8+ T cells in Peanut Allergic Individuals. The Journal of allergy and clinical immunology Yu, W., Zhou, X., Dunham, D., Lyu, S. C., Manohar, M., Zhang, W., Zhao, F., Davis, M. M., Nadeau, K. 2019
Abstract

CD8+ T cells are seldom considered in IgE mediated food allergy; we show that peanut specific CD8+ T cells are increased in peanut allergic human subjects.

View details for PubMedID 30682458
Changing Patient Mindsets About Non-Life-Threatening Symptoms During Oral Immunotherapy: A Randomized Clinical Trial. The journal of allergy and clinical immunology. In practice Howe, L. C., Leibowitz, K. A., Perry, M. A., Bitler, J. M., Block, W., Kaptchuk, T. J., Nadeau, K. C., Crum, A. J. 2019
Abstract

BACKGROUND: Oral immunotherapy (OIT) can lead to desensitization to food allergens, but patients can experience treatment-related symptoms of allergic reactions that cause anxiety and treatment dropout. Interventions to improve OIT for patients are needed.OBJECTIVE: To determine whether fostering the mindset that non-life-threatening symptoms during OIT can signal desensitization improves treatment experience and outcomes.METHODS: In a randomized, blinded, controlled phase II study, 50 children/adolescents (28% girls, aged 7-17, M=10.82, SD=3.01) completed six-month OIT for peanut allergies. Patients and their parent(s) had monthly clinic visits at the Sean N. Parker Center for Allergy & Asthma Research between 1/5/2017-8/3/2017. All families received identical symptom management training. In a 1:1 approach, 24 patients and their families were informed that non-life-threatening symptoms during OIT were unfortunate side effects of treatment, and 26 patients and their families were informed that non-life-threatening symptoms could signal desensitization. Families participated in activities to reinforce these symptom mindsets.RESULTS: Compared to families informed that symptoms are side effects, families informed that symptoms can signal desensitization were less anxious (B=-0.46, 95% CI (-0.76 to -0.16), p=0.003), less likely to contact staff about symptoms (5/24[9.4%] vs. 27/154[17.5%] instances, p=0.036), experienced fewer non-life-threatening symptoms as doses increased (BInteraction=-0.54(-0.83 to -0.27), p<0.001), less likely to skip/reduce doses (1/26[4%] vs. 5/24[21%] patients, p=0.065), and showed greater increase in patient peanut-specific blood IgG4 levels (BInteraction=0.76(0.36 to 1.17), p<0.001).CONCLUSION: Fostering the mindset that symptoms can signal desensitization improves OIT experience and outcomes. Changing how providers inform patients about non-life-threatening symptoms is a promising avenue for improving treatment.

View details for PubMedID 30682576
Prenatal exposure to mercury in relation to infant infections and respiratory symptoms in the New Hampshire Birth Cohort Study. Environmental research Emeny, R. T., Korrick, S. A., Li, Z., Nadeau, K., Madan, J., Jackson, B., Baker, E., Karagas, M. R. 2019; 171: 523?29
Abstract

BACKGROUND: Mechanistic studies support the potential for mercury (Hg) to alter immunity, including via in utero exposure. As yet, there are few prospective studies of in utero Hg exposure and subsequent immune-related outcomes, especially in infancy.OBJECTIVES: We investigated the association of biomarkers of prenatal Hg exposure and maternal silver-mercury dental amalgams with the occurrence of infant allergy, respiratory infection, and respiratory symptoms in the first year of life.METHODS: The New Hampshire Birth Cohort Study (NHBCS) ascertained information on infant allergies, infections and symptoms through telephone interviews at 4, 8 and 12 months postpartum and measured total Hg in maternal toenails collected at ~28-30 weeks gestation. Information on maternal fish consumption and presence of dental amalgams was obtained from a questionnaire administered at study enrollment at 24-28 weeks. A total of 1321 NHBCS mother-infant pairs had at least one Hg exposure measure (toenail Hg or information on dental amalgams) and information on dietary fish intake. Generalized linear models and generalized estimating equation models with Poisson regression adjusted for potential confounders (maternal age, level of education, parity, smoking, alternative Healthy Eating Index-2010, infant sex, gestational age, feeding mode, and day care attendance) were used to assess the association between infant outcomes and prenatal toenail Hg levels. We subsetted this analysis on mothers who consumed fish (n?=?706) as a measure of in utero methylmercury (MeHg) exposure. Associations between infant outcomes and dental amalgams as a measure of in utero inorganic Hg exposure were assessed among mothers who did not consume fish (n?=?218).RESULTS: Among women who ate fish during pregnancy, higher maternal toenail Hg concentrations were associated with an increased risk of lower respiratory infections and respiratory symptoms requiring a doctor visit among infants age 9-12?months (relative risk (RR) 1.4 (95% CI: 1.1, 1.9) and 1.2 (95% CI: 1.0, 1.4) respectively), whereas a reduced risk of lower respiratory infections was observed among infants 0-4?months of age (RR?=?0.7 (95% CI: 0.5, 1.0). We found little to no evidence of associations of toenail Hg with upper respiratory infections, allergy or eczema at any age to one year. Among infants of mothers who did not consume fish, we found an elevated risk of upper respiratory infections requiring a doctor visit in relation to having dental amalgams during pregnancy (RR?=?1.5 (95% CI: 1.1, 2.1)). Overall, weaker associations were observed with lower respiratory infections, respiratory symptoms, and medically confirmed allergies, and there was no association with eczema.CONCLUSIONS: Our analyses of a US birth cohort, along with prior mechanistic work, raise the possibility that gestational Hg exposure through fish/seafood consumption and dental amalgams may alter respiratory infections and respiratory symptoms in infants.

View details for DOI 10.1016/j.envres.2019.01.026

View details for PubMedID 30743244
Report from the National Institute of Allergy and Infectious Diseases Workshop on "Atopic Dermatitis and the Atopic March: Mechanisms and Interventions". The Journal of allergy and clinical immunology Davidson, W. F., Leung, D. Y., Beck, L. A., Berin, C. M., Boguniewicz, M., Busse, W. W., Chatila, T. A., Geha, R. S., Gern, J. E., Guttman-Yassky, E., Irvine, A. D., Kim, B. S., Kong, H. H., Lack, G., Nadeau, K. C., Schwaninger, J., Simpson, A., Simpson, E. L., Spergel, J. M., Togias, A., Wahn, U., Wood, R. A., Woodfolk, J. A., Ziegler, S. F., Plaut, M. 2019
Abstract

Atopic dermatitis (AD) affects up to 20% of children world-wide and is an increasing public health problem particularly in developed countries. Although AD in infants and young children can resolve, there is a well-recognized, increased risk of sequential progression from AD to other atopic diseases including food allergy, allergic rhinitis, allergic asthma and allergic rhinoconjunctivitis; a process referred to as the "atopic march". The mechanisms underlying the development of AD and subsequent progression to other atopic comorbidities, particularly food allergy, are incompletely understood and the subject of intense investigation. Other major research objectives are the development of effective strategies to prevent AD and food allergy as well as therapeutic interventions to inhibit the atopic march. In 2017, the Division of Allergy, Immunology and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop to discuss current understanding and important advances in these research areas and to identify gaps in knowledge and future research directions. International and national experts in the field were joined by representatives from several National Institutes of Health institutes. Summaries of workshop presentations, key conclusions and recommendations are presented herein.

View details for PubMedID 30639346
Identification of Almond (Prunus dulcis) Vicilin As a Food Allergen JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY Che, H., Zhang, Y., Lyu, S., Nadeau, K. C., McHugh, T. 2019; 67 (1): 425?32
Abstract

Almond is one of the tree nuts listed by US FDA as a food allergen source. A food allergen identified with patient sera has been debated to be the 2S albumin or the 7S vicilin. However, neither of these proteins has been defined as a food allergen. The purpose of this study was to clone, express, and purify almond vicilin and test whether it is a food allergen. Western blot experiment was performed with 18 individual sera from patients with double-blind, placebo-controlled clinical almond allergy. The results showed that 44% of the sera contained IgE antibodies that recognized the recombinant almond vicilin, indicating that it is an almond allergen. Identifying this and additional almond allergens will facilitate the understanding of the allergenicity of seed proteins in tree nuts and their cross-reactivity.

View details for DOI 10.1021/acs.jafc.8b05290

View details for Web of Science ID 000455561500045

View details for PubMedID 30512943
Prevalence and Severity of Food Allergies Among US Adults. JAMA network open Gupta, R. S., Warren, C. M., Smith, B. M., Jiang, J., Blumenstock, J. A., Davis, M. M., Schleimer, R. P., Nadeau, K. C. 2019; 2 (1): e185630
Abstract

Importance: Food allergy is a costly, potentially life-threatening condition. Although studies have examined the prevalence of childhood food allergy, little is known about prevalence, severity, or health care utilization related to food allergies among US adults.Objective: To provide nationally representative estimates of the distribution, severity, and factors associated with adult food allergies.Design, Setting, and Participants: In this cross-sectional survey study of US adults, surveys were administered via the internet and telephone from October 9, 2015, to September 18, 2016. Participants were first recruited from NORC at the University of Chicago's probability-based AmeriSpeak panel, and additional participants were recruited from the non-probability-based Survey Sampling International (SSI) panel.Exposures: Demographic and allergic participant characteristics.Main Outcomes and Measures: Self-reported food allergies were the main outcome and were considered convincing if reported symptoms to specific allergens were consistent with IgE-mediated reactions. Diagnosis history to specific allergens and food allergy-related health care use were also primary outcomes. Estimates were based on this nationally representative sample using small-area estimation and iterative proportional fitting methods. To increase precision, AmeriSpeak data were augmented by calibration-weighted, non-probability-based responses from SSI.Results: Surveys were completed by 40?443 adults (mean [SD] age, 46.6 [20.2] years), with a survey completion rate of 51.2% observed among AmeriSpeak panelists (n=7210) and 5.5% among SSI panelists (n=33?233). Estimated convincing food allergy prevalence among US adults was 10.8% (95% CI, 10.4%-11.1%), although 19.0% (95% CI, 18.5%-19.5%) of adults self-reported a food allergy. The most common allergies were shellfish (2.9%; 95% CI, 2.7%-3.1%), milk (1.9%; 95% CI, 1.8%-2.1%), peanut (1.8%; 95% CI, 1.7%-1.9%), tree nut (1.2%; 95% CI, 1.1%-1.3%), and fin fish (0.9%; 95% CI, 0.8%-1.0%). Among food-allergic adults, 51.1% (95% CI, 49.3%-52.9%) experienced a severe food allergy reaction, 45.3% (95% CI, 43.6%-47.1%) were allergic to multiple foods, and 48.0% (95% CI, 46.2%-49.7%) developed food allergies as an adult. Regarding health care utilization, 24.0% (95% CI, 22.6%-25.4%) reported a current epinephrine prescription, and 38.3% (95% CI, 36.7%-40.0%) reported at least 1 food allergy-related lifetime emergency department visit.Conclusions and Relevance: These data suggest that at least 10.8% (>26 million) of US adults are food allergic, whereas nearly 19% of adults believe that they have a food allergy. Consequently, these findings suggest that it is crucial that adults with suspected food allergy receive appropriate confirmatory testing and counseling to ensure food is not unnecessarily avoided and quality of life is not unduly impaired.

View details for PubMedID 30646188
Prevalence and Severity of Food Allergies Among US Adults JAMA NETWORK OPEN Gupta, R. S., Warren, C. M., Smith, B. M., Jiang, J., Blumenstock, J. A., Davis, M. M., Schleimer, R. P., Nadeau, K. C. 2019; 2 (1)
View details for DOI 10.1001/jamanetworkopen.2018.5630

View details for Web of Science ID 000465422700029
Sustained Successful Peanut Oral Immunotherapy Associated with Low Basophil Activation and Peanut-Specific IgE. The Journal of allergy and clinical immunology Tsai, M., Mukai, K., Chinthrajah, R. S., Nadeau, K. C., Galli, S. J. 2019
Abstract

Oral immunotherapy (OIT) can successfully desensitize many peanut allergic subjects, but clinical tolerance diminishes over time upon discontinuation, or low dose maintenance, of peanut. Therefore, in order to improve the efficacy and sustainability of such therapy, we sought to identify biomarkers and clinical tools that can predict therapeutic outcomes and monitor treatment responses.We evaluated whether basophil activation in whole blood, and plasma levels of peanut-specific immunoglobulins, are useful biomarkers for peanut OIT.We longitudinally measured, before, during and after OIT, basophil activation in whole blood ex vivo in response to peanut stimulation, and peanut-specific IgE and IgG4, in a large, single-site, double-blind, randomized, placebo-controlled, phase 2 peanut OIT study. We compared basophil responsiveness and peanut specific immunoglobulins between those who were clinically reactive vs. tolerant to peanut oral challenges.Peanut OIT significantly decreased basophil activation, peanut-specific, Ara h 1, Ara h 2 and Ara h 3 IgEs, and sIgE/total IgE, but increased sIgG4/sIgE. Participants who became reactive to 4 g of peanut 13 weeks off active OIT exhibited higher peanut-induced basophil activation ex vivo and higher peanut-specific IgEs and sIgE/total IgE, but lower sIgG4/sIgE. Notably, participants entering the study with low basophil responsiveness were more likely to achieve treatment success. Substantial suppression of basophil activation was required to maintain long-term clinical tolerance after peanut OIT.Assessments of peanut-specific basophil activation and peanut-specific immunoglobulins can help to predict treatment outcomes, and to differentiate transient desensitization vs. sustained unresponsiveness after OIT.

View details for DOI 10.1016/j.jaci.2019.10.038

View details for PubMedID 31805311
Global metabolic profiling to model biological processes of aging in twins. Aging cell Bunning, B. J., Contrepois, K., Lee-McMullen, B., Dhondalay, G. K., Zhang, W., Tupa, D., Raeber, O., Desai, M., Nadeau, K. C., Snyder, M. P., Andorf, S. 2019: e13073
Abstract

Aging is intimately linked to system-wide metabolic changes that can be captured in blood. Understanding biological processes of aging in humans could help maintain a healthy aging trajectory and promote longevity. We performed untargeted plasma metabolomics quantifying 770 metabolites on a cross-sectional cohort of 268 healthy individuals including 125 twin pairs covering human lifespan (from 6�months to 82�years). Unsupervised clustering of metabolic profiles revealed 6 main aging trajectories throughout life that were associated with key metabolic pathways such as progestin steroids, xanthine metabolism, and long-chain fatty acids. A random forest (RF) model was successful to predict age in adult subjects (?16�years) using 52 metabolites (R2 �=�.97). Another RF model selected 54 metabolites to classify pediatric and adult participants (out-of-bag error�=�8.58%). These RF models in combination with correlation network analysis were used to explore biological processes of healthy aging. The models highlighted established metabolites, like steroids, amino acids, and free fatty acids as well as novel metabolites and pathways. Finally, we show that metabolic profiles of twins become more dissimilar with age which provides insights into nongenetic age-related variability in metabolic profiles in response to environmental exposure.

View details for DOI 10.1111/acel.13073

View details for PubMedID 31746094
Can food allergy be cured? What are the future prospects? Allergy Sampath, V., Sindher, S. B., Alvarez Pinzon, A. M., Nadeau, K. C. 2019
Abstract

Food allergies have become a significant heath burden as prevalence continues to rise, affecting 6-13% of the global population. In the absence of drugs approved by regulatory agencies, the current standard of care remains avoidance of allergenic foods and management of acute allergic reactions with antihistamines and epinephrine auto-injectors. Allergen immunotherapy has been shown to increase the threshold of reactivity in the majority of food-allergic individuals. However, challenges include long treatment periods, high rates of adverse reactions, and lack of permanence of desensitization and established protocols. To address these limitations, adjunctive allergen-specific immunotherapy, vaccines, and non-allergen specific therapies (e.g., monoclonal antibodies) are being explored. The future of food allergy treatment is promising with a number of clinical trials in progress. Currently, although desensitization can be achieved for the majority of individuals with food allergy through immunotherapy, continued ingestion of allergen is needed for most individuals to maintain desensitization. Further understanding of the mechanisms of food allergy and identification of biomarkers to distinguish between temporary and permanent resolution of allergies is needed before a cure, where reactivity to the allergen is permanently lost enabling the individual to consume the allergen in any amount at any time, can be envisioned.

View details for DOI 10.1111/all.14116

View details for PubMedID 31733120
Natural Tr1-like cells do not confer long-term tolerogenic memory. eLife Yadava, K., Medina, C. O., Ishak, H., Gurevich, I., Kuipers, H., Shamskhou, E. A., Koliesnik, I. O., Moon, J. J., Weaver, C., Nadeau, K. C., Bollyky, P. L. 2019; 8
Abstract

IL-10-producing Tr1 cells promote tolerance but their contributions to tolerogenic memory are unclear. Using 10BiT mice that carry a Foxp3-eGFP reporter and stably express CD90.1 following IL-10 production, we characterized the spatiotemporal dynamics of Tr1 cells in a house dust mite model of allergic airway inflammation. CD90.1+Foxp3-IL-10+ Tr1 cells arise from memory cells and rejoin the tissue-resident memory T-cell pool after cessation of IL-10 production. Persistent antigenic stimulation is necessary to sustain IL-10 production and Irf1 and Batf expression distinguishes CD90.1+Foxp3-IL-10+ Tr1 cells from CD90.1+Foxp3-IL-10- 'former' Tr1. Depletion of Tr1-like cells after primary sensitization exacerbates allergic airway inflammation. However, neither transfer nor depletion of former Tr1 cells influences either Tr1 numbers or the inflammatory response during subsequent allergen memory re-challenge weeks later. Together these data suggest that naturally-arising Tr1 cells do not necessarily give rise to more Tr1 upon allergen re-challenge or contribute to tolerogenic memory. This phenotypic instability may limit efforts to re-establish tolerance by expanding Tr1 in vivo.

View details for DOI 10.7554/eLife.44821

View details for PubMedID 31603425
Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study. Lancet (London, England) Chinthrajah, R. S., Purington, N., Andorf, S., Long, A., O'Laughlin, K. L., Lyu, S. C., Manohar, M., Boyd, S. D., Tibshirani, R., Maecker, H., Plaut, M., Mukai, K., Tsai, M., Desai, M., Galli, S. J., Nadeau, K. C. 2019
Abstract

Dietary avoidance is recommended for peanut allergies. We evaluated the sustained effects of peanut allergy oral immunotherapy (OIT) in a randomised long-term study in adults and children.In this randomised, double-blind, placebo-controlled, phase 2 study, we enrolled participants at the Sean N Parker Center for Allergy and Asthma Research at Stanford University (Stanford, CA, USA) with peanut allergy aged 7-55 years with a positive result from a double-blind, placebo-controlled, food challenge (DBPCFC; ?500 mg of peanut protein), a positive skin-prick test (SPT) result (?5 mm wheal diameter above the negative control), and peanut-specific immunoglobulin (Ig)E concentration of more than 4 kU/L. Participants were randomly assigned (2�4:1�4:1) in a two-by-two block design via a computerised system to be built up and maintained on 4000 mg peanut protein through to week 104 then discontinued on peanut (peanut-0 group), to be built up and maintained on 4000 mg peanut protein through to week 104 then to ingest 300 mg peanut protein daily (peanut-300 group) for 52 weeks, or to receive oat flour (placebo group). DBPCFCs to 4000 mg peanut protein were done at baseline and weeks 104, 117, 130, 143, and 156. The pharmacist assigned treatment on the basis of a randomised computer list. Peanut or placebo (oat) flour was administered orally and participants and the study team were masked throughout by use of oat flour that was similar in look and feel to the peanut flour and nose clips, as tolerated, to mask taste. The statistician was also masked. The primary endpoint was the proportion of participants who passed DBPCFCs to a cumulative dose of 4000 mg at both 104 and 117 weeks. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02103270.Between April 15, 2014, and March 2, 2016, of 152 individuals assessed, we enrolled 120 participants, who were randomly assigned to the peanut-0 (n=60), peanut-300 (n=35), and placebo groups (n=25). 21 (35%) of peanut-0 group participants and one (4%) placebo group participant passed the 4000 mg challenge at both 104 and 117 weeks (odds ratio [OR] 12�7, 95% CI 1�8-554�8; p=0�0024). Over the entire study, the most common adverse events were mild gastrointestinal symptoms, which were seen in 90 of 120 patients (50/60 in the peanut-0 group, 29/35 in the peanut-300 group, and 11/25 in the placebo group) and skin disorders, which were seen in 50/120 patients (26/60 in the peanut-0 group, 15/35 in the peanut-300 group, and 9/25 in the placebo group). Adverse events decreased over time in all groups. Two participants in the peanut groups had serious adverse events during the 3-year study. In the peanut-0 group, in which eight (13%) of 60 participants passed DBPCFCs at week 156, higher baseline peanut-specific IgG4 to IgE ratio and lower Ara h 2 IgE and basophil activation responses were associated with sustained unresponsiveness. No treatment-related deaths occurred.Our study suggests that peanut OIT could desensitise individuals with peanut allergy to 4000 mg peanut protein but discontinuation, or even reduction to 300 mg daily, could increase the likelihood of regaining clinical reactivity to peanut. Since baseline blood tests correlated with week 117 treatment outcomes, this study might aid in optimal patient selection for this therapy.National Institute of Allergy and Infectious Diseases.

View details for DOI 10.1016/S0140-6736(19)31793-3

View details for PubMedID 31522849
ICER report for peanut OIT comes up short. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology Eiwegger, T., Anagnostou, K., Arasi, S., B�gin, P., Ben-Shoshan, M., Beyer, K., Blumchen, K., Brough, H., Caubet, J. C., Chan, E. S., Chinthrajah, S., Davis, C. M., Roches, A. D., Du Toit, G., Elizur, A., Galli, S. J., H�land, G., Hoffmann-Sommergruber, K., Kim, H., Leung, D. Y., Muraro, A., Nurmatov, U. B., Pajno, G. B., Sindher, S., Szepfalusi, Z., Torres, M. J., Upton, J., Worm, M., Nadeau, K. 2019
View details for DOI 10.1016/j.anai.2019.09.001

View details for PubMedID 31513908
A Phase 2 Randomized Controlled Multisite Study Using Omalizumab-facilitated Rapid Desensitization to Test Continued vs Discontinued Dosing in Multifood Allergic Individuals. EClinicalMedicine Andorf, S., Purington, N., Kumar, D., Long, A., O'Laughlin, K. L., Sicherer, S., Sampson, H., Cianferoni, A., Whitehorn, T. B., Petroni, D., Makhija, M., Robison, R. G., Lierl, M., Logsdon, S., Desai, M., Galli, S. J., Rael, E., Assa'ad, A., Chinthrajah, S., Pongracic, J., Spergel, J. M., Tam, J., Tilles, S., Wang, J., Nadeau, K. 2019; 7: 27?38
Abstract

As there is limited data on the sustainability of desensitization of multifood-oral immunotherapy (multifood-OIT), we conducted a multisite multifood-OIT study to compare the efficacy of successful desensitization with sustained dosing vs discontinued dosing after multifood-OIT.We enrolled 70 participants, aged 5-22?years with multiple food allergies confirmed by double-blind placebo-controlled food challenges (DBPCFCs). In the open-label phase of the study, all participants received omalizumab (weeks 1-16) and multi-OIT (2-5 allergens; weeks 8-30) and eligible participants (on maintenance dose of each allergen by weeks 28-29) were randomized 1:1:1 to 1?g, 300?mg, or 0?mg arms (blinded, weeks 30-36) and then tested by food challenge at week 36. Success was defined as passing 2?g food challenge to at least 2 foods in week 36.Most participants were able to reach a dose of 2?g or higher of each of 2, 3, 4, and 5 food allergens (as applicable to the participant's food allergens in OIT) in week 36 food challenges. Using an intent-to-treat analysis, we did not find evidence that a 300?mg dose was effectively different than a 1?g dose in maintaining desensitization, and both together were more effective than OIT discontinuation (0?mg dose) (85% vs 55%, P?=?0.03). Fifty-five percent of the intent-to-treat participants and 69% of per protocol participants randomized to the 0?mg arm showed no objective reactivity after 6?weeks of discontinuation. Cross-desensitization was found between cashew/pistachio and walnut/pecan when only one of the foods was part of OIT. No statistically significant safety differences were found between the three arms.These results suggest that sustained desensitization after omalizumab-facilitated multi-OIT best occurs through continued maintenance OIT dosing of either 300?mg or 1?g of each food allergen as opposed to discontinuation of multi-OIT.Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Jeff and MacKenzie Bezos, NIAID AADCRC U19AI104209.ClinicalTrials.gov number, NCT02626611.

View details for DOI 10.1016/j.eclinm.2018.12.006

View details for PubMedID 31193674

View details for PubMedCentralID PMC6537534
Modeling Cardiovascular Risks of E-Cigarettes With Human-Induced Pluripotent Stem Cell-Derived Endothelial Cells. Journal of the American College of Cardiology Lee, W. H., Ong, S. G., Zhou, Y., Tian, L., Bae, H. R., Baker, N., Whitlatch, A., Mohammadi, L., Guo, H., Nadeau, K. C., Springer, M. L., Schick, S. F., Bhatnagar, A., Wu, J. C. 2019; 73 (21): 2722?37
Abstract

Electronic cigarettes (e-cigarettes) have experienced a tremendous increase in use. Unlike cigarette smoking, the effects of e-cigarettes and their constituents on mediating vascular health remain understudied. However, given their increasing popularity, it is imperative to evaluate the health risks of e-cigarettes, including the effects of their ingredients, especially nicotine and flavorings.The purpose of this study was to investigate the effects of flavored e-cigarette liquids (e-liquids) and serum isolated from e-cigarette users on endothelial health and endothelial cell-dependent macrophage activation.Human-induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) and a high-throughput screening approach were used to assess endothelial integrity following exposure to 6 different e-liquids with varying nicotine concentrations and to serum from e-cigarette users.The cytotoxicity of the e-liquids varied considerably, with the cinnamon-flavored product being most potent and leading to significantly decreased cell viability, increased reactive oxygen species (ROS) levels, caspase 3/7 activity, and low-density lipoprotein uptake, activation of oxidative stress-related pathway, and impaired tube formation and migration, confirming endothelial dysfunction. Upon exposure of ECs to e-liquid, conditioned media induced macrophage polarization into a pro-inflammatory state, eliciting the production of interleukin-1? and -6, leading to increased ROS. After exposure of human iPSC-ECs to serum of e-cigarette users, increased ROS linked to endothelial dysfunction was observed, as indicated by impaired pro-angiogenic properties. There was also an observed increase in inflammatory cytokine expression in the serum of e-cigarette users.Acute exposure to flavored e-liquids or e-cigarette use exacerbates endothelial dysfunction, which�often precedes cardiovascular diseases.

View details for DOI 10.1016/j.jacc.2019.03.476

View details for PubMedID 31146818
High-affinity allergen-specific human antibodies cloned from single IgE B cell transcriptomes. Science (New York, N.Y.) Croote, D., Darmanis, S., Nadeau, K. C., Quake, S. R. 2018; 362 (6420): 1306?9
Abstract

Immunoglobulin E (IgE) antibodies protect against helminth infections but can also cause life-threatening allergic reactions. Despite their role in human health, the cells that produce these antibodies are rarely observed and remain enigmatic. We isolated single IgE B cells from individuals with food allergies and used single-cell RNA sequencing to elucidate the gene expression and splicing patterns unique to these cells. We identified a surprising example of convergent evolution in which IgE antibodies underwent identical gene rearrangements in unrelated individuals. Through the acquisition of variable region mutations, these IgE antibodies gained high affinity and unexpected cross-reactivity to the clinically important peanut allergens Ara h 2 and Ara h 3. These findings provide insight into IgE B cell transcriptomics and enable biochemical dissection of this antibody class.

View details for PubMedID 30545888
High-affinity allergen-specific human antibodies cloned from single IgE B cell transcriptomes SCIENCE Croote, D., Darmanis, S., Nadeau, K. C., Quake, S. R. 2018; 362 (6420): 1306-+
View details for DOI 10.1126/science.aau2599

View details for Web of Science ID 000452994400056
Predicting development of sustained unresponsiveness to milk oral immunotherapy using epitope-specific antibody binding profiles. The Journal of allergy and clinical immunology Suarez-Farinas, M., Suprun, M., Chang, H. L., Gimenez, G., Grishina, G., Getts, R., Nadeau, K., Wood, R. A., Sampson, H. A. 2018
Abstract

BACKGROUND: In a recent trial of milk oral immunotherapy (MOIT) with or without omalizumab in 55 patients with milk allergy treated for 28months, 44 of 55 subjects passed a 10-g desensitization milk protein challenge; 23 of 55 subjects passed the 10-g sustained unresponsiveness (SU) challenge 8weeks after discontinuing MOIT.OBJECTIVE: We sought to determine whether IgE and IgG4 antibody binding to allergenic milk protein epitopes changes with MOIT and whether this could predict the development of SU.METHODS: By using a novel high-throughput Luminex-based assay to quantitate IgE and IgG4 antibody binding to 66 sequential epitopes on 5 milk proteins, serum samples from 47 subjects were evaluated before and after MOIT. Machine learning strategies were used to predict whether a subject would have SU after 8weeks of MOIT discontinuation.RESULTS: MOIT profoundly altered IgE and IgG4 binding to epitopes, regardless of treatment outcome. At the initiation of MOIT, subjects achieving SU exhibited significantly less antibody binding to 40 allergenic epitopes than subjects who were desensitized only (false discovery rate?0.05 and fold change>1.5). Based on baseline epitope-specific antibody binding, we developed predictive models of SU. Using simulations, we show that, on average, IgE-binding epitopes alone perform significantly better than models using standard serum component proteins (average area under the curve, >97% vs 80%). The optimum model using 6 IgE-binding epitopes achieved a 95% area under the curve and 87% accuracy.CONCLUSION: Despite the relatively small sample size, we have shown that by measuring the epitope repertoire, we can build reliable models to predict the probability of SU after MOIT. Baseline epitope profiles appear more predictive of MOIT response than those based on serum component proteins.

View details for PubMedID 30528770
The Public Health Impact of Parent-Reported Childhood Food Allergies in the United States PEDIATRICS Gupta, R. S., Warren, C. M., Smith, B. M., Blumenstock, J. A., Jiang, J., Davis, M. M., Nadeau, K. C. 2018; 142 (6)
View details for DOI 10.1542/peds.2018-1235

View details for Web of Science ID 000451372200017
Analysis of a Large Standardized Food Challenge Data Set to Determine Predictors of Positive Outcome Across Multiple Allergens FRONTIERS IN IMMUNOLOGY Sindher, S., Long, A. J., Purington, N., Chollet, M., Slatkin, S., Andorf, S., Tupa, D., Kumar, D., Woch, M. A., O'Laughlin, K. L., Assaad, A., Pongracic, J., Spergel, J. M., Tam, J., Tilles, S., Wang, J., Galli, S. J., Nadeau, K. C., Chinthrajah, R. 2018; 9
View details for DOI 10.3389/fimmu.2018.02689

View details for Web of Science ID 000451447100001
Laundry detergents and detergent residue after rinse directly disrupt tight junction barrier integrity in human bronchial epithelial cells. The Journal of allergy and clinical immunology Wang, M., Tan, G., Eljaszewicz, A., Meng, Y., Wawrzyniak, P., Acharya, S., Altunbulakli, C., Westermann, P., Dreher, A., Yan, L., Wang, C., Akdis, M., Zhang, L., Nadeau, K. C., Akdis, C. A. 2018
Abstract

BACKGROUND: Defects in epithelial barrier have recently been associated with asthma and other allergies. The influence of laundry detergents on human bronchial epithelial cells (HBECs) and their barrier function remain unknown.OBJECTIVE: We investigated the effects of laundry detergents on cytotoxicity, barrier function, transcriptome and epigenome in HBECs.METHODS: Air-liquid interface cultures of primary HBECs from healthy control subjects, asthma and chronic obstructive pulmonary disease patients were exposed to laundry detergents and detergent residue after rinse. The cytotoxicity and epithelial barrier function were evaluated. RNA sequencing, assay for transposase accessible chromatin with high-throughput sequencing and DNA methylation arrays were used for checking transcriptome and epigenome.RESULTS: Laundry detergents and rinse residue showed dose dependent toxic effect to HBECs with irregular cell shape and leakage of lactate dehydrogenase after 24h exposure. A disrupted epithelial barrier function was found with decreased transepithelial electric resistance, increased paracellular flux and stratified tight junction immunostaining in HBECs exposed to laundry detergent at 1:25,000 dilutions or rinse residue at further 1:10 dilutions. RNA sequencing analysis showed that lipid metabolism, apoptosis progress and epithelial-derived alarmins related genes were up-regulated, while cell adhesion related genes were down-regulated by laundry detergent at 1:50,000 dilutions after 24h exposure without substantially affecting chromatin accessibility and DNA methylation.CONCLUSION: Our data demonstrate that laundry detergents even at a very high dilution and rinse residue show significant cell toxic and directly disruptive effects on the tight junction barrier integrity of HBECs without affecting the epigenome and tight junction genes expression.

View details for PubMedID 30500342
Baseline Gastrointestinal Eosinophilia Is Common in Oral Immunotherapy Subjects With IgE-Mediated Peanut Allergy FRONTIERS IN IMMUNOLOGY Wright, B. L., Fernandez-Becker, N. Q., Kambham, N., Purington, N., Tupa, D., Zhang, W., Rank, M. A., Kita, H., Shim, K. P., Bunning, B. J., Doyle, A. D., Jacobsen, E. A., Boyd, S. D., Tsai, M., Maecker, H., Manohar, M., Galli, S. J., Nadeau, K. C., Chinthrajah, R. 2018; 9
View details for DOI 10.3389/fimmu.2018.02624

View details for Web of Science ID 000450901300001
The Public Health Impact of Parent-Reported Childhood Food Allergies in the United States. Pediatrics Gupta, R. S., Warren, C. M., Smith, B. M., Blumenstock, J. A., Jiang, J., Davis, M. M., Nadeau, K. C. 2018
Abstract

: media-1vid110.1542/5840360268001PEDS-VA_2018-1235Video Abstract BACKGROUND: Childhood food allergy (FA) is a life-threatening chronic condition that substantially impairs quality of life. This large, population-based survey estimates childhood FA prevalence and severity of all major allergenic foods. Detailed allergen-specific information was also collected regarding FA management and health care use.METHODS: A survey was administered to US households between 2015 and 2016, obtaining parent-proxy responses for 38408 children. Prevalence estimates were based on responses from NORC at the University of Chicago's nationally representative, probability-based AmeriSpeak Panel (51% completion rate), which were augmented by nonprobability-based responses via calibration weighting to increase precision. Prevalence was estimated via weighted proportions. Multiple logistic regression models were used to evaluate FA predictors.RESULTS: Overall, estimated current FA prevalence was 7.6% (95% confidence interval: 7.1%-8.1%) after excluding 4% of children whose parent-reported FA reaction history was inconsistent with immunoglobulin E-mediated FA. The most prevalent allergens were peanut (2.2%), milk (1.9%), shellfish (1.3%), and tree nut (1.2%). Among food-allergic children, 42.3% reported ?1 severe FA and 39.9% reported multiple FA. Furthermore, 19.0% reported ?1 FA-related emergency department visit in the previous year and 42.0% reported ?1 lifetime FA-related emergency department visit, whereas 40.7% had a current epinephrine autoinjector prescription. Prevalence rates were higher among African American children and children with atopic comorbidities.CONCLUSIONS: FA is a major public health concern, affecting 8% of US children. However, >11% of children were perceived as food-allergic, suggesting that the perceived disease burden may be greater than previously acknowledged.

View details for PubMedID 30455345
Differences in multiple immune parameters between Indian and US infants PLOS ONE Rathore, D. K., Holmes, T. H., Nadeau, K. C., Mittal, P., Batra, A., Rosenberg-Hasson, Y., Sopory, S., Gupta, R., Chellani, H. K., Aggarwal, K. C., Bal, V., Natchu, U., Bhatnagar, S., Tavassoli, M., Lyell, D. J., Rath, S., Wadhwa, N., Maecker, H. T. 2018; 13 (11)
View details for DOI 10.1371/journal.pone.0207297

View details for Web of Science ID 000450420900025
IgE blockade during food allergen ingestion enhances the induction of inhibitory IgG antibodies. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology Stranks, A. J., Minnicozzi, S. C., Miller, S. J., Burton, O. T., Logsdon, S. L., Spergel, J. M., Nadeau, K. C., Pongracic, J. A., Umetsu, D. T., Rachid, R., MacGinnitie, A. J., Schneider, L., Oettgen, H. C. 2018
View details for DOI 10.1016/j.anai.2018.10.024

View details for PubMedID 30404033
Multicenter, randomized, double-blind, placebo-controlled clinical trial of vital wheat gluten oral immunotherapy. The Journal of allergy and clinical immunology Nowak-Wegrzyn, A., Wood, R. A., Nadeau, K. C., Pongracic, J. A., Henning, A. K., Lindblad, R. W., Beyer, K., Sampson, H. A. 2018
Abstract

BACKGROUND: Wheat is a common food allergen that can cause anaphylaxis.OBJECTIVE: We sought to determine the efficacy and safety of vital wheat gluten (VWG) oral immunotherapy (OIT).METHODS: After baseline double-blind, placebo-controlled food challenge (DBPCFC), 46 patients with wheat allergy (median age, 8.7years; range, 4.2-22.3years) were randomized 1:1 to low-dose VWG OIT or placebo, with biweekly escalation to 1445mg of wheat protein (WP). After a year 1 DBPCFC, active subjects continued low-dose VWG OIT for another year and underwent a year 2 DBPCFC and, if passed, a subsequent off-therapy DBPCFC. Placebo-treated subjects crossed over to high-dose VWG OIT (maximum, 2748mg of WP).RESULTS: The median baseline successfully consumed dose (SCD) was 43mg of WP in both groups. At year 1, 12 (52.2%) of 23 low-dose VWG OIT-treated and 0 (0%) of 23 placebo-treated subjects achieved the primary end point of an SCD of 4443mg of WP or greater (P<.0001); median SCDs were 4443 and 143mg, respectively. At year 2, 7 (30.4%) of 23 low-dose VWG OIT-treated subjects were desensitized to an SCD of 7443mg of WP; 3 (13%) achieved sustained unresponsiveness 8 to 10weeks off therapy. Among placebo-treated subjects who crossed over to high-dose VWG OIT, 12 (57.1%) of 21 were desensitized after 1year (median SCD, 7443mg of WP; nonsignificant vs low-dose VWG OIT). At year 1, skin prick test responses and wheat- and omega-5 gliadin-specific IgE levels did not differ between groups; the low-dose VWG OIT median specific IgG4 level was greater than placebo (wheat, P=.0005; omega-5 gliadin, P=.0001). Year 1 SCDs correlated with wheat-specific (rho=0.55, P=.0003) and omega-5 gliadin-specific (rho=0.51, P=.001) IgG4 levels in all subjects. Among 7822 low-dose VWG OIT doses in year 1, 15.4% were associated with adverse reactions: 0.04% were severe, and 0.08% subjects received epinephrine. Among 7921 placebo doses, 5.8% were associated with adverse reactions; none were severe.CONCLUSIONS: Low- and high-dose VWG OIT induced desensitization in about one half of the subjects after 1year of treatment. Two years of low-dose VWG OIT resulted in 30% desensitization, and 13% had sustained unresponsiveness.

View details for DOI 10.1016/j.jaci.2018.08.041

View details for PubMedID 30389226
Peanut-specific T cell responses in patients with different clinical reactivity PLOS ONE Birrueta, G., Tripple, V., Pham, J., Manohar, M., James, E. A., Kwok, W. W., Nadeau, K. C., Sette, A., Peters, B., Schulten, V. 2018; 13 (10)
View details for DOI 10.1371/journal.pone.0204620

View details for Web of Science ID 000446921100058
The Use of Biomarkers to Predict Aero-Allergen and Food Immunotherapy Responses CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY Sindher, S. B., Long, A., Acharya, S., Sampath, V., Nadeau, K. C. 2018; 55 (2): 190?204
View details for DOI 10.1007/s12016-018-8678-z

View details for Web of Science ID 000446688000007
Eliciting Dose and Safety Outcomes From a Large Dataset of Standardized Multiple Food Challenges FRONTIERS IN IMMUNOLOGY Purington, N., Chinthrajah, R., Long, A., Sindher, S., Andorf, S., O'Laughlin, K., Woch, M. A., Scheiber, A., Assa'ad, A., Pongracic, J., Spergel, J. M., Tam, J., Tilles, S., Wang, J., Galli, S. J., Desai, M., Nadeau, K. C. 2018; 9
View details for DOI 10.3389/fimmu.2018.02057

View details for Web of Science ID 000445235300001
Comparison of sublingual immunotherapy and oral immunotherapy in peanut allergy ALLERGO JOURNAL Zhang, W., Sindher, S. B., Sampath, V., Nadeau, K. 2018; 27 (6): 22?30
View details for DOI 10.1007/s40629-018-0067-x

View details for Web of Science ID 000455982000009
Realizing the Paris Climate Agreement to Improve Cardiopulmonary Health Where Science Meets Policy ANNALS OF THE AMERICAN THORACIC SOCIETY Rice, M. B., Malea, N., Pinkerton, K. E., Schwartz, J., Nadeau, K. C., Browner, C. M., Whitehouse, S., Thurston, G. D. 2018; 15 (7): 791?98
View details for DOI 10.1513/AnnalsATS.201803-203PS

View details for Web of Science ID 000437045300004

View details for PubMedID 29652522
High dimensional immune biomarkers demonstrate differences in phenotypes and endotypes in food allergy and asthma ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY Chinthrajah, R., Purington, N., Sampath, V., Andorf, S., Manohar, M., Prunicki, M., Zhou, X., Tupa, D., Nadeau, K. C. 2018; 121 (1): 117?19
View details for DOI 10.1016/j.anai.2018.04.022

View details for Web of Science ID 000436596100021
Development of a tool predicting severity of allergic reaction during peanut challenge ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY Chinthrajah, R., Purington, N., Andorf, S., Rosa, J. S., Mukai, K., Hamilton, R., Smith, B., Gupta, R., Galli, S. J., Desai, M., Nadeau, K. C. 2018; 121 (1): 69-+
View details for DOI 10.1016/j.anai.2018.04.020

View details for Web of Science ID 000436596100014
Heterogeneity of Ara h Component-Specific CD4 T Cell Responses in Peanut-Allergic Subjects FRONTIERS IN IMMUNOLOGY Renand, A., Farrington, M., Whalen, E., Wambre, E., Bajzik, V., Chinthrajah, S., Nadeau, K. C., Kwok, W. W. 2018; 9
View details for DOI 10.3389/fimmu.2018.01408

View details for Web of Science ID 000436138800001
Impact of allergen immunotherapy in allergic asthma IMMUNOTHERAPY Zhang, W., Lin, C., Sampath, V., Nadeau, K. 2018; 10 (7): 579?93
View details for DOI 10.2217/imt-2017-0138

View details for Web of Science ID 000434066200006
Isotype-specific agglutination-PCR (ISAP): Asensitive and multiplex method for measuring allergen-specific IgE. The Journal of allergy and clinical immunology Tsai, C., Mukai, K., Robinson, P. V., Gray, M. A., Waschmann, M. B., Lyu, S., Tsai, M., Chinthrajah, R. S., Nadeau, K. C., Bertozzi, C. R., Galli, S. J. 2018; 141 (5): 1901
View details for PubMedID 29248495
Isotype-specific agglutination-PCR (ISAP): A sensitive and multiplex method for measuring allergen-specific IgE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Tsai, C., Mukai, K., Robinson, P. V., Gray, M. A., Waschmann, M. B., Lyu, S., Tsai, M., Chinthrajah, R. S., Nadeau, K. C., Bertozzi, C. R., Galli, S. J. 2018; 141 (5): 1901-+
View details for DOI 10.1016/j.jaci.2017.11.021

View details for Web of Science ID 000432148200038
Development of a tool predicting severity of allergic reaction during peanut challenge. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology Chinthrajah, R. S., Purington, N., Andorf, S., Rosa, J. S., Mukai, K., Hamilton, R., Smith, B. M., Gupta, R., Galli, S. J., Desai, M., Nadeau, K. C. 2018
Abstract

BACKGROUND: Reliable prognostic markers for predicting severity of allergic reactions during oral food challenges (OFC) have not been established.OBJECTIVE: We sought to develop a predictive algorithm of a food challenge severity score (CSS) to identify those at higher risk for severe reactions to a standardized peanut OFC.METHODS: Medical history and allergy tests were obtained for 120 peanut-allergic participants who underwent double-blind, placebo-controlled food challenges (DBPCFCs). Reactions were assigned a CSS between 1 to 6 based on cumulative tolerated dose and a "severity clinical indicator." Demographic characteristics, clinical features, peanut component IgE values, and a basophil activation marker were considered in a multi-step analysis to derive a flexible decision rule to understand risk during peanut of OFC.RESULTS: 18.3% participants had a severe reaction (CSS >4). The decision rule identified the following three variables (in order of importance) as predictors of reaction severity: ratio of %CD63hi stimulation with peanut to %CD63hi anti-IgE (CD63 ratio), history of exercise-induced asthma, and forced expiratory volume in 1 sec/forced vital capacity (FEV1/FVC) ratio. The CD63 ratio alone was a strong predictor of CSS (p<0.001).CONCLUSION: The CSS is a novel tool that combines dose thresholds and allergic reactions to understand risks associated with peanut OFCs. Lab-values (CD63 ratio), along with clinical variables (exercise-induced asthma and FEV1/FVC ratio) contribute to the predictive ability of the severity of reaction to peanut OFC. Further testing of this decision rule is needed in a larger external data source before it can be considered outside of research settings.

View details for PubMedID 29709643
High dimensional immune biomarkers demonstrate differences in phenotypes and endotypes in food allergy and asthma. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology Chinthrajah, R. S., Purington, N., Sampath, V., Andorf, S., Manohar, M., Prunicki, M., Zhou, X., Tupa, D., Nadeau, K. C. 2018
View details for PubMedID 29705381
Epigenetic Changes in Immune Cells Following Successful Desensitization with Multi-Food Allergen Oral Immunotherapy Chinthrajah, S., Andorf, S., Manohar, M., Maecker, H., Tsai, M., Galli, S., Nadeau, K. SPRINGER/PLENUM PUBLISHERS. 2018: 358?59
View details for Web of Science ID 000431311600075
Impact of allergen immunotherapy in allergic asthma. Immunotherapy Zhang, W., Lin, C., Sampath, V., Nadeau, K. 2018
Abstract

Although traditional pharmacological approaches improve outcomes in disease management for allergic asthma, these fail to modify the underlying immune responses. Allergen immunotherapy remains the only etiological therapy for the treatment of respiratory allergies for which clinical efficacy has been demonstrated through several well-controlled studies. In this review, we examine evidence from the past 5 years regarding the impact of allergen immunotherapy on allergic asthma to inform practitioners and stimulate further discussion and research.

View details for PubMedID 29569506
New treatment directions in food allergy ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY Sampath, V., Sindher, S. B., Zhang, W., Nadeau, K. C. 2018; 120 (3): 254?62
View details for PubMedID 29508712
The Use of Biomarkers to Predict Aero-Allergen and Food Immunotherapy Responses. Clinical reviews in allergy & immunology Sindher, S. B., Long, A., Acharya, S., Sampath, V., Nadeau, K. C. 2018
Abstract

The incidence of allergic conditions has continued to rise over the past several decades, with a growing body of research dedicated toward the treatment of such conditions. By driving a complex range of changes in the underlying immune response, immunotherapy is the only therapy that modulates the immune system with long-term effects and is presently utilized for the treatment of several atopic conditions. Recent efforts have focused on identifying biomarkers associated with these changes that may be of use in predicting patients with the highest likelihood of positive clinical outcomes during allergen immunotherapy (AIT), providing guidance regarding AIT discontinuation, and predicting symptomatic relapse and the need for booster AIT after therapy. The identification of such biomarkers in food allergy has the additional benefit of replacing oral food challenges, which are presently the gold standard for diagnosing food allergies. While several markers have shown early promise, research has yet to identify a marker that can invariably predict clinical response to AIT. Skin prick testing (SPT) and specific IgE have commonly been used as inclusion criteria for the initiation of AIT and prediction of reactions during subsequent allergen challenge; however, existing data suggests that changes in these markers are not always associated with clinical improvement and can be widely variable, reducing their utility in predicting clinical response. Similar findings have been described for the use of allergen-specific functional IgG4 antibodies, basophil activation and histamine release, and type 2 innate lymphoid cells. There appears to be a promising association between changes in the expression of dendritic cell-associated markers, as well as the use of DNA promoter region methylation patterns in the prediction of allergy status following therapy. The cellular and molecular changes brought about by immunotherapy are still under investigation, but major strides in our understanding are being made.

View details for PubMedID 29455358
Socioeconomic Variables Associated with Immune Biomarkers in Asthmatic Children Nyarko-Odoom, A. O., Prunicki, M., Zhang, W., Zhou, X., Nadeau, K. C. MOSBY-ELSEVIER. 2018: AB74
View details for Web of Science ID 000429306700234
Changes in Binding Patterns of Cashew-Specific IgE and IgG4 Over the Course of Oral Immunotherapy with Omalizumab Stankey, C. T., Andorf, S., Tetteh, A., Chinthrajah, S., Nadeau, K. C. MOSBY-ELSEVIER. 2018: AB246
View details for Web of Science ID 000429306700774
Anti-IgE treatment with oral immunotherapy in multifood allergic participants: a double-blind, randomised, controlled trial LANCET GASTROENTEROLOGY & HEPATOLOGY Andorf, S., Purington, N., Block, W. M., Long, A. J., Tupa, D., Brittain, E., Spergel, A., Desai, M., Galli, S. J., Nadeau, K. C., Chinthrajah, R. 2018; 3 (2): 85?94
Abstract

Despite progress in single food oral immunotherapy, there is little evidence concerning the safety and efficacy of treating individuals with multiple food (multifood) allergies. We did a pilot study testing whether anti-IgE (omalizumab) combined with multifood oral immunotherapy benefited multifood allergic patients.We did a blinded, phase 2 clinical trial at Stanford University. We enrolled participants, aged 4-15 years, with multifood allergies validated by double-blind, placebo-controlled food challenges to their offending foods. Inclusion criteria included a positive skin prick test of 6 mm or more (wheal diameter, above the negative control), a food-specific serum IgE concentration of more than 4 kU/L for each food, or both, and a positive double-blind, placebo-controlled food challenge at 500 mg or less of food protein. Exclusion criteria included eosinophilic oesophagitis and severe asthma. Participants were randomised (3:1) with a block size of four, to receive multifood oral immunotherapy to two to five foods, together with omalizumab (n=36) or placebo (n=12). 12 individuals who fulfilled the same inclusion and exclusion criteria were included as controls. These individuals were not randomised and received neither omalizumab nor oral immunotherapy. Omalizumab or placebo was administered subcutaneously for 16 weeks, with oral immunotherapy starting at week 8, and was stopped 20 weeks before the exit double-blind, placebo-controlled food challenge at week 36. The primary endpoint was the proportion of participants who passed double-blind, placebo-controlled food challenges to at least two of their offending foods. This completed trial is registered with ClinicalTrials.gov, number NCT02643862.Between March 25, 2015, and Aug 18, 2016, 165 participants were assessed for eligibility, of whom 84 did not meet the inclusion criteria and 21 declined to participate. We enrolled and randomised 48 eligible participants and the remaining 12 patients were included as nonrandomised, untreated controls. At week 36, a significantly greater proportion of the omalizumab-treated (30 [83%] of 36) versus placebo (four [33%] of 12) participants passed double-blind, placebo-controlled food challenges to 2 g protein for two or more of their offending foods (odds ratio 10�0, 95% CI 1�8-58�3, p=0�0044). All participants completed the study. There were no serious or severe (grade 3 or worse) adverse events. Participants in the omalizumab group had a significantly lower median per-participant percentage of oral immunotherapy doses associated with any adverse events (27% vs 68%; p=0�0082). The most common adverse events in both groups were gastrointestinal events.In multifood allergic patients, omalizumab improves the efficacy of multifood oral immunotherapy and enables safe and rapid desensitisation.US National Institutes of Health (NIH).

View details for PubMedID 29242014
Exposure to NO2, CO, and PM2.5 is linked to regional DNA methylation differences in asthma CLINICAL EPIGENETICS Prunicki, M., Stell, L., Dinakarpandian, D., de Planell-Saguer, M., Lucas, R. W., Hammond, S., Balmes, J. R., Zhou, X., Paglino, T., Sabatti, C., Miller, R. L., Nadeau, K. C. 2018; 10: 2
Abstract

DNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs). Further identification of specific CpG sites and the pollutants that are associated with methylation of these CpG sites in immune cells could impact our understanding of asthma pathophysiology. In this study, we sought to identify some CpG sites in specific genes that could be associated with asthma regulation (Foxp3 and IL10) and to identify the different AAPs for which exposure prior to the blood draw is linked to methylation levels at these sites. We recruited subjects from Fresno, California, an area known for high levels of AAPs. Blood samples and responses to questionnaires were obtained (n?=?188), and in a subset of subjects (n?=?33), repeat samples were collected 2�years later. Average measures of AAPs were obtained for 1, 15, 30, 90, 180, and 365�days prior to each blood draw to estimate the short-term vs. long-term effects of the AAP exposures.Asthma was significantly associated with higher differentially methylated regions (DMRs) of the Foxp3 promoter region (p?=?0.030) and the IL10 intronic region (p?=?0.026). Additionally, at the 90-day time period (90�days prior to the blood draw), Foxp3 methylation was positively associated with NO2, CO, and PM2.5 exposures (p?=?0.001, p?=?0.001, and p?=?0.012, respectively). In the subset of subjects retested 2�years later (n?=?33), a positive association between AAP exposure and methylation was sustained. There was also a negative correlation between the average Foxp3 methylation of the promoter region and activated Treg levels (p?=?0.039) and a positive correlation between the average IL10 methylation of region 3 of intron 4 and IL10 cytokine expression (p?=?0.030).Short-term and long-term exposures to high levels of CO, NO2, and PM2.5 were associated with alterations in differentially methylated regions of Foxp3. IL10 methylation showed a similar trend. For any given individual, these changes tend to be sustained over time. In addition, asthma was associated with higher differentially methylated regions of Foxp3 and IL10.

View details for PubMedID 29317916
Food allergy and omics. The Journal of allergy and clinical immunology Dhondalay, G. K., Rael, E., Acharya, S., Zhang, W., Sampath, V., Galli, S. J., Tibshirani, R., Boyd, S. D., Maecker, H., Nadeau, K. C., Andorf, S. 2018; 141 (1): 20?29
Abstract

Food allergy (FA) prevalence has been increasing over the last few decades and is now a global health concern. Current diagnostic methods for FA result in a high number of false-positive results, and the standard of care is either allergen avoidance or use of epinephrine on accidental exposure, although currently with no other approved treatments. The increasing prevalence of FA, lack of robust biomarkers, and inadequate treatments warrants further research into the mechanism underlying food allergies. Recent technological advances have made it possible to move beyond traditional biological techniques to more sophisticated high-throughput approaches. These technologies have created the burgeoning field of omics sciences, which permit a more systematic investigation of biological problems. Omics sciences, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, and exposomics, have enabled the construction of regulatory networks and biological pathway models. Parallel advances in bioinformatics and computational techniques have enabled the integration, analysis, and interpretation of these exponentially growing data sets and opens the possibility of personalized or precision medicine for FA.

View details for PubMedID 29307411
Comparison of sublingual immunotherapy and oral immunotherapy in peanut allergy. Allergo journal international Zhang, W., Sindher, S. B., Sampath, V., Nadeau, K. 2018; 27 (6): 153?61
Abstract

The prevalence of food allergy has been increasing over the past few decades at an alarming rate with peanut allergy affecting about 2% of children. Both oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) have shown promise as a treatment option for peanut allergy. Immunotherapy induces desensitization and reduces the risk of reaction during accidental ingestion and may also enable those who are successfully desensitized to include the food allergen in their diet. OIT has been very well studied and has been found to be more efficacious that SLIT with an acceptable safety profile. However, SLIT is associated with fewer side effects. Studies indicate that a combination of SLIT and OIT may together induce a significant increase in challenge thresholds with fewer adverse events. More head-to-head clinical trials that direct compare OIT and SLIT as well as SLIT and OIT combination studies are warranted.

View details for DOI 10.1007/s40629-018-0067-x

View details for PubMedID 31440440

View details for PubMedCentralID PMC6705598
Differences in multiple immune parameters between Indian and U.S. infants. PloS one Rathore, D. K., Holmes, T. H., Nadeau, K. C., Mittal, P., Batra, A., Rosenberg-Hasson, Y., Sopory, S., Gupta, R., Chellani, H. K., Aggarwal, K. C., Bal, V., Natchu, U. C., Bhatnagar, S., Tavassoli, M., Lyell, D. J., Rath, S., Wadhwa, N., Maecker, H. T. 2018; 13 (11): e0207297
Abstract

To compare immune phenotypes across two geographic and ethnic communities, we examined umbilical cord blood by flow cytometry and Luminex in parallel cohorts of 53 newborns from New Delhi, India, and 46 newborns from Stanford, California. We found that frequencies of a B cell subset suggested to be B-1-like, and serum IgM concentration were both significantly higher in the Stanford cohort, independent of differences in maternal age. While serum IgA levels were also significantly higher in the Stanford cohort, IgG1, IgG2, and IgG4 were significantly higher in the New Delhi samples. We found that neutrophils, plasmacytoid dendritic cells, CD8+ T cells, and total T cells were higher in the U.S. cohort, while dendritic cells, patrolling monocytes (CD14dimCD16+), natural killer cells, CD4+ T cells, and naive B cells were higher in the India cohort. Within the India cohort, we also identified cell types whose frequency was positively or negatively predictive of occurrence of infection(s) in the first six months of life. Monocytes, total T cells, and memory CD4+ T cells were most prominent in having an inverse relationship with infection. We suggest that these data provide impetus for follow-up studies linking phenotypic differences to environmental versus genetic factors, and to infection outcomes.

View details for PubMedID 30444901
Peanut-specific T cell responses in patients with different clinical reactivity. PloS one Birrueta, G., Tripple, V., Pham, J., Manohar, M., James, E. A., Kwok, W. W., Nadeau, K. C., Sette, A., Peters, B., Schulten, V. 2018; 13 (10): e0204620
Abstract

Whole extract or allergen-specific IgE testing has become increasingly popular in the diagnosis of peanut allergy. However, much less is known about T cell responses in peanut allergy and how it relates to different clinical phenotypes. CD4+ T cells play a major role in the pathophysiology of peanut allergy as well as tolerance induction during oral desensitization regimens. We set out to characterize and phenotype the T cell responses and their targets in peanut sensitized patients. Using PBMC from peanut-allergic and non-allergic patients, we mapped T cell epitopes for three major peanut allergens, Ara h 1, 2 and 3 (27 from Ara h 1, 4 from Ara h 2 and 43 from Ara h 3) associated with release of IFNgamma (representative Th1 cytokine) and IL5 (representative Th2 cytokine). A pool containing 19 immunodominant peptides, selected to account for 60% of the total Ara h 1-3-specific T cell response in allergics, but only 20% in non-allergics, was shown to discriminate T cell responses in peanut-sensitized, symptomatic vs non-symptomatic individuals more effectively than peanut extract. This pool elicited positive T cell responses above a defined threshold in 12/15 sensitized, symptomatic patients, whereas in the sensitized but non-symptomatic cohort only, 4/14 reacted. The reactivity against this peptide pool in symptomatic patients was dominated by IL-10, IL-17 and to a lesser extend IL-5. For four distinct epitopes, HLA class II restrictions were determined, enabling production of tetrameric reagents. Tetramer staining in four donors (2 symptomatic, 2 non-symptomatic) revealed a trend for increased numbers of peanut epitope-specific T cells in symptomatic patients compared to non-symptomatic patients, which was associated with elevated CRTh2 expression whereas cells from non-symptomatic patients exhibited higher levels of Integrin beta7 expression. Our results demonstrate differences in T cell response magnitude, epitope specificity and phenotype between symptomatic and non-symptomatic peanut-sensitized patients. In addition to IgE reactivity, analysis of peanut-specific T cells may be useful to improve our understanding of different clinical manifestations in peanut allergy.

View details for PubMedID 30304054
Eliciting Dose and Safety Outcomes From a Large Dataset of Standardized Multiple Food Challenges. Frontiers in immunology Purington, N., Chinthrajah, R. S., Long, A., Sindher, S., Andorf, S., O'Laughlin, K., Woch, M. A., Scheiber, A., Assa'ad, A., Pongracic, J., Spergel, J. M., Tam, J., Tilles, S., Wang, J., Galli, S. J., Desai, M., Nadeau, K. C. 2018; 9: 2057
Abstract

Background: Food allergy prevalence has continued to rise over the past decade. While studies have reported threshold doses for multiple foods, large-scale multi-food allergen studies are lacking. Our goal was to identify threshold dose distributions and predictors of severe reactions during blinded oral food challenges (OFCs) in multi-food allergic patients. Methods: A retrospective chart review was performed on all Stanford-initiated clinical protocols involving standardized screening OFCs to any of 11 food allergens at 7 sites. Interval-censoring survival analysis was used to calculate eliciting dose (ED) curves for each food. Changes in severity and ED were also analyzed among participants who had repeated challenges to the same food. Results: Of 428 participants, 410 (96%) had at least one positive challenge (1445 standardized OFCs with 1054 total positive challenges). Participants undergoing peanut challenges had the highest ED50 (29.9 mg), while those challenged with egg or pistachio had the lowest (7.07 or 1.7 mg, respectively). The most common adverse event was skin related (54%), followed by gastrointestinal (GI) events (33%). A history of asthma was associated with a significantly higher risk of a severe reaction (hazard ratio [HR]: 2.37, 95% confidence interval [CI]: 1.36, 4.13). Higher values of allergen-specific IgE (sIgE) and sIgE to total IgE ratio (sIgEr) were also associated with higher risk of a severe reaction (1.49 [1.19, 1.85] and 1.84 [1.30, 2.59], respectively). Participants undergoing cashew, peanut, pecan, sesame, and walnut challenges had more severe reactions as ED increased. In participants who underwent repeat challenges, the ED did not change (p = 0.66), but reactions were more severe (p = 0.02). Conclusions: Participants with a history of asthma, high sIgEr, and/or high values of sIgE were found to be at higher risk for severe reactions during food challenges. These findings may help to optimize food challenge dosing schemes in multi-food allergic, atopic patients, specifically at lower doses where the majority of reactions occur. Trials Registration Number: ClinicalTrials. gov number NCT03539692; https://clinicaltrials.gov/ct2/show/NCT03539692.

View details for PubMedID 30298065
Analysis of a Large Standardized Food Challenge Data Set to Determine Predictors of Positive Outcome Across Multiple Allergens. Frontiers in immunology Sindher, S., Long, A. J., Purington, N., Chollet, M., Slatkin, S., Andorf, S., Tupa, D., Kumar, D., Woch, M. A., O'Laughlin, K. L., Assaad, A., Pongracic, J., Spergel, J. M., Tam, J., Tilles, S., Wang, J., Galli, S. J., Nadeau, K. C., Chinthrajah, R. S. 2018; 9: 2689
Abstract

Background: Double-blind placebo-controlled food challenges (DBPCFCs) remain the gold standard for the diagnosis of food allergy; however, challenges require significant time and resources and place the patient at an increased risk for severe allergic adverse events. There have been continued efforts to identify alternative diagnostic methods to replace or minimize the need for oral food challenges (OFCs) in the diagnosis of food allergy. Methods: Data was extracted for all IRB-approved, Stanford-initiated clinical protocols involving standardized screening OFCs to a cumulative dose of 500 mg protein to any of 11 food allergens in participants with elevated skin prick test (SPT) and/or specific IgE (sIgE) values to the challenged food across 7 sites. Baseline population characteristics, biomarkers, and challenge outcomes were analyzed to develop diagnostic criteria predictive of positive OFCs across multiple allergens in our multi-allergic cohorts. Results: A total of 1247 OFCs completed by 427 participants were analyzed in this cohort. Eighty-five percent of all OFCs had positive challenges. A history of atopic dermatitis and multiple food allergies were significantly associated with a higher risk of positive OFCs. The majority of food-specific SPT, sIgE, and sIgE/total IgE (tIgE) thresholds calculated from cumulative tolerated dose (CTD)-dependent receiver operator curves (ROC) had high discrimination of OFC outcome (area under the curves > 0.75). Participants with values above the thresholds were more likely to have positive challenges. Conclusions: This is the first study, to our knowledge, to not only adjust for tolerated allergen dose in predicting OFC outcome, but to also use this method to establish biomarker thresholds. The presented findings suggest that readily obtainable biomarker values and patient demographics may be of use in the prediction of OFC outcome and food allergy. In the subset of patients with SPT or sIgE values above the thresholds, values appear highly predictive of a positive OFC and true food allergy. While these values are relatively high, they may serve as an appropriate substitute for food challenges in clinical and research settings.

View details for PubMedID 30538699
Heterogeneity of Ara h Component-Specific CD4 T Cell Responses in Peanut-Allergic Subjects. Frontiers in immunology Renand, A., Farrington, M., Whalen, E., Wambre, E., Bajzik, V., Chinthrajah, S., Nadeau, K. C., Kwok, W. W. 2018; 9: 1408
Abstract

Understanding the peanut-specific CD4 T cell responses in peanut-allergic (PA) subjects should provide new insights into the development of innovative immunotherapies for the treatment of peanut allergy. Although peanut-specific CD4 T cells have a TH2 profile in PA subjects, the immunogenicity of different Ara h components in eliciting specific CD4 T cell responses and the heterogeneity of these Ara h-reactive TH2 cells remains unclear. In this study, we investigated Ara h 1, 2, 3, 6, and 8-specific T cell responses in PA and sensitized non-peanut-allergic (sNPA) subjects, using the CD154 upregulation assay and the class II tetramer technology. In the PA group, T cells directed against Ara h 1, 2, 3, and 6 have a heterogeneous TH2 phenotype characterized by differential expression of CRTH2, CD27, and CCR6. Reactivity toward these different components was also distinct for each PA subject. Two dominant Ara h 2 epitopes associated with DR1501 and DR0901 were also identified. Frequencies of Ara h-specific T cell responses were also linked to the peanut specific-IgE level. Conversely, low peanut-IgE level in sNPA subjects was associated with a weak or an absence of the allergen-specific T cell reactivity. Ara h 8-specific T cell reactivity was weak in both PA and sNPA subjects. Thus, peanut-IgE level was associated with a heterogeneous Ara h (but not Ara h 8)-specific T cell reactivity only in PA patients. This suggests an important immunogenicity of each Ara h 1, 2, 3, and 6 in inducing peanut allergy. Targeting Ara h 1-, 2-, 3-, and 6-specific effector-TH2 cells can be the future way to treat peanut allergy.

View details for PubMedID 29988522
Baseline Gastrointestinal Eosinophilia Is Common in Oral Immunotherapy Subjects With IgE-Mediated Peanut Allergy. Frontiers in immunology Wright, B. L., Fernandez-Becker, N. Q., Kambham, N., Purington, N., Tupa, D., Zhang, W., Rank, M. A., Kita, H., Shim, K. P., Bunning, B. J., Doyle, A. D., Jacobsen, E. A., Boyd, S. D., Tsai, M., Maecker, H., Manohar, M., Galli, S. J., Nadeau, K. C., Chinthrajah, R. S. 2018; 9: 2624
Abstract

Rationale: Oral immunotherapy (OIT) is an emerging treatment for food allergy. While desensitization is achieved in most subjects, many experience gastrointestinal symptoms and few develop eosinophilic gastrointestinal disease. It is unclear whether these subjects have subclinical gastrointestinal eosinophilia (GE) at baseline. We aimed to evaluate the presence of GE in subjects with food allergy before peanut OIT. Methods: We performed baseline esophagogastroduodenoscopies on 21 adults before undergoing peanut OIT. Subjects completed a detailed gastrointestinal symptom questionnaire. Endoscopic findings were assessed using the Eosinophilic Esophagitis (EoE) Endoscopic Reference Score (EREFS) and biopsies were obtained from the esophagus, gastric antrum, and duodenum. Esophageal biopsies were evaluated using the EoE Histologic Scoring System. Immunohistochemical staining for eosinophil peroxidase (EPX) was also performed. Hematoxylin and eosin and EPX stains of each biopsy were assessed for eosinophil density and EPX/mm2 was quantified using automated image analysis. Results: All subjects were asymptomatic. Pre-existing esophageal eosinophilia (>5 eosinophils per high-power field [eos/hpf]) was present in five participants (24%), three (14%) of whom had >15 eos/hpf associated with mild endoscopic findings (edema, linear furrowing, or rings; median EREFS = 0, IQR 0-0.25). Some subjects also demonstrated basal cell hyperplasia, dilated intercellular spaces, and lamina propria fibrosis. Increased eosinophils were noted in the gastric antrum (>12 eos/hpf) or duodenum (>26 eos/hpf) in 9 subjects (43%). EPX/mm2 correlated strongly with eosinophil counts (r = 0.71, p < 0.0001). Conclusions: Pre-existing GE is common in adults with IgE-mediated peanut allergy. Eosinophilic inflammation (EI) in these subjects may be accompanied by mild endoscopic and histologic findings. Longitudinal data collection during OIT is ongoing.

View details for PubMedID 30524424
Peanut-specific type 1 regulatory T cells induced in vitro from allergic subjects are functionally impaired JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Pellerin, L., Jenks, J., Chinthrajah, S., Dominguez, T., Block, W., Zhou, X., Noshirvan, A., Gregori, S., Roncarolo, M., Nadeau, K., Bacchetta, R. 2018; 141 (1): 202-+
Abstract

Peanut allergy (PA) is a life-threatening condition that lacks regulator-approved treatment. Regulatory T type 1 (TR1) cells are potent suppressors of immune responses and can be induced in�vivo upon repeated antigen exposure or in�vitro by using tolerogenic dendritic cells. Whether oral immunotherapy (OIT) leads to antigen-specific TR1 cell induction has not been established.We sought to determine whether peanut-specific TR1 cells can be generated in�vitro from peripheral blood of patients with PA at baseline or during OIT and whether they are functional compared with peanut-specific TR1 cells induced from healthy control (HC) subjects.Tolerogenic dendritic cells were differentiated in the presence of IL-10 from PBMCs of patients with PA and HC subjects pulsed with the main peanut allergens of Arachis hypogaea, Ara h 1 and 2, and used as antigen-presenting cells for autologous CD4+ T cells (CD4+ T cells coincubated with tolerogenic dendritic cells pulsed with the main peanut allergens [pea-T10�cells]). Pea-T10�cells were characterized by the presence of CD49b+ lymphocyte-activation gene 3 (LAG3)+ TR1 cells, antigen-specific proliferative responses, and cytokine production.CD49b+LAG3+ TR1 cells were induced in pea-T10�cells at comparable percentages from HC subjects and patients with PA. Despite their antigen specificity, pea-T10�cells of patients with PA with or without OIT, as compared with those of HC subjects, were not anergic and had high TH2 cytokine production upon peanut-specific restimulation.Peanut-specific TR1 cells can be induced from HC subjects and patients with PA, but those from patients with PA are functionally defective independent of OIT. The unfavorable�TR1/TH2 ratio is discussed as a possible cause of�PA�TR1 cell impairment.

View details for PubMedID 28689791
Observational long-term follow-up study of rapid food oral immunotherapy with omalizumab ALLERGY ASTHMA AND CLINICAL IMMUNOLOGY Andorf, S., Manohar, M., Dominguez, T., Block, W., Tupa, D., Kshirsagar, R. A., Sampath, V., Chinthrajah, R., Nadeau, K. C. 2017; 13: 51
Abstract

A number of clinical studies focused on treating a single food allergy through oral immunotherapy (OIT) with adjunctive omalizumab treatment have been published. We previously demonstrated safety and tolerability of a rapid OIT protocol using omalizumab in a phase 1 study to achieve desensitization to multiple (up to 5) food allergens in parallel, rapidly (7-36�weeks; median�=�18�weeks). In the current long-term, observational study, we followed 34 food allergic participants for over 5�years, who had originally undergone the phase 1 rapid OIT protocol.After reaching the maintenance dose of 2�g protein for each of their respective food allergens as a part of the phase 1 study, the long-term maintenance dose was reduced for some participants based on a pragmatic team-based decision. Participants were followed up to 62�months through standard oral food challenges (OFCs), skin prick tests, and blood tests.Each participant passed the 2�g OFC to each of their offending food allergens (up to 5 food allergens in total) at the end of the long-term follow-up (LTFU) study.Our data demonstrate the feasibility of long-term maintenance dosing of a food allergen without compromising the desensitized status conferred through rapid-OIT. Trial registration Registry: Clinicaltrials.gov. Registration numbers: NCT01510626 (original study), NCT03234764 (LTFU study). Date of registration: November 29, 2011 (original study); July 26, 2017 (LTFU study, retrospectively registered).

View details for PubMedID 29296107

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Feasibility of sustained response through long-term dosing in food allergy immunotherapy ALLERGY ASTHMA AND CLINICAL IMMUNOLOGY Andorf, S., Manohar, M., Dominguez, T., Block, W., Tupa, D., Kshirsagar, R. A., Sampath, V., Chinthrajah, R., Nadeau, K. C. 2017; 13: 52
Abstract

Clinical trials using oral immunotherapy (OIT) for the treatment of food allergies have shown promising results. We previously demonstrated the feasibility of desensitization for up to 5 food allergens simultaneously through OIT. In this observational study, we report the findings of long-term follow-up (LTFU) of the participants treated through a single site OIT phase 1 trial.The participants (n�=�46) were followed up to 72�months since the time they reached 2�g maintenance dose per food in the initial phase 1 trial. During the long-term maintenance dosing, participants continued or reduced the initial maintenance dose of food allergen protein to high (median 2�g protein) vs. low (median 300�mg protein). Participant follow-up included clinical monitoring, standardized OFCs, and in some cases, skin prick tests and measurement of allergen-specific IgE and IgG4.Irrespective of the high vs. low long-term maintenance dose during LTFU, all participants were able to ingest 2�g protein of each food allergen protein during OFCs performed at the end of our LTFU.Our LTFU cohort of food OIT participants from a single site, phase 1 OIT study, supports the feasibility of sustained desensitization through long-term maintenance dosing. Trial registration Registry: Clinicaltrial.gov. Registration numbers: NCT01490177 (original study); NCT03234764 (LTFU study). Date of registration: November 29, 2011 (original study); July 26, 2017 (LTFU study, registered).

View details for PubMedID 29296108

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Effect of Varying Doses of Epicutaneous Immunotherapy vs Placebo on Reaction to Peanut Protein Exposure Among Patients With Peanut Sensitivity A Randomized Clinical Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Sampson, H. A., Shreffler, W. G., Yang, W. H., Sussman, G. L., Brown-Whitehorn, T. F., Nadeau, K. C., Cheema, A. S., Leonard, S. A., Pongracic, J. A., Sauvage-Delebarre, C., Assa'ad, A. H., de Blay, F., Bird, J., Tilles, S. A., Boralevi, F., Bourrier, T., Hebert, J., Green, T. D., van Wijk, R., Knulst, A. C., Kanny, G., Schneider, L. C., Kowalski, M. L., Dupont, C. 2017; 318 (18): 1798?1809
Abstract

Epicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed only in preclinical and early human trials.To determine the optimal dose, adverse events (AEs), and efficacy of a peanut patch for peanut allergy treatment.Phase 2b double-blind, placebo-controlled, dose-ranging trial of a peanut patch in peanut-allergic patients (6-55 years) from 22 centers, with a 2-year, open-label extension (July 31, 2012-July 31, 2014; extension completed September 29, 2016). Patients (n?=?221) had peanut sensitivity and positive double-blind, placebo-controlled food challenges to an eliciting dose of 300 mg or less of peanut protein.Randomly assigned patients (1:1:1:1) received an epicutaneous peanut patch containing 50 ?g (n?=?53), 100 ?g (n?=?56), or 250 ?g (n?=?56) of peanut protein or a placebo patch (n?=?56). Following daily patch application for 12 months, patients underwent a double-blind, placebo-controlled food challenge to establish changes in eliciting dose.The primary efficacy end point was percentage of treatment responders (eliciting dose: ?10-times increase and/or reaching ?1000 mg of peanut protein) in each group vs placebo patch after 12 months. Secondary end points included percentage of responders by age strata and treatment-emergent adverse events (TEAEs).Of 221 patients randomized (median age, 11 years [quartile 1, quartile 3: 8, 16]; 37.6% female), 93.7% completed the trial. A significant absolute difference in response rates was observed at month 12 between the 250-?g (n?=?28; 50.0%) and placebo (n?=?14; 25.0%) patches (difference, 25.0%; 95% CI, 7.7%-42.3%; P?=?.01). No significant difference was seen between the placebo patch vs the 100-?g patch. Because of statistical testing hierarchical rules, the 50-?g patch was not compared with placebo. Interaction by age group was only significant for the 250-?g patch (P?=?.04). In the 6- to 11-year stratum, the response rate difference between the 250-?g (n?=?15; 53.6%) and placebo (n?=?6; 19.4%) patches was 34.2% (95% CI, 11.1%-57.3%; P?=?.008); adolescents/adults showed no difference between the 250-?g (n?=?13; 46.4%) and placebo (n?=?8; 32.0%) patches: 14.4% (95% CI, -11.6% to 40.4%; P?=?.40). No dose-related serious AEs were observed. The percentage of patients with 1 or more TEAEs (largely local skin reactions) was similar across all groups in year 1: 50-?g patch?=?100%, 100-?g patch?=?98.2%, 250-?g patch?=?100%, and placebo patch?=?92.9%. The overall median adherence was 97.6% after 1 year; the dropout rate for treatment-related AEs was 0.9%.In this dose-ranging trial of peanut-allergic patients, the 250-?g peanut patch resulted in significant treatment response vs placebo patch following 12 months of therapy. These findings warrant a phase 3 trial.clinicaltrials.gov Identifier: NCT01675882.

View details for PubMedID 29136445

View details for PubMedCentralID PMC5820709
Combining anti-IgE with oral immunotherapy PEDIATRIC ALLERGY AND IMMUNOLOGY Lin, C., Lee, I. T., Sampath, V., Dinakar, C., DeKruyff, R. H., Schneider, L. C., Nadeau, K. 2017; 28 (7): 619?27
Abstract

Food allergy is a significant medical problem that affects up to 8% of children in developed countries. At present, there are no curative therapies available in routine practice and management of food allergy involves strict allergen avoidance, education, and prompt treatment upon accidental exposure. Oral immunotherapy (OIT) is an efficacious experimental approach to food allergy and has been shown to provide a substantial benefit in terms of allergen desensitization. However, OIT is associated with high rates of allergic reactions, and the period of protection offered by OIT appears to be limited and highly variable. Recurrence of allergen sensitivity after a period of treatment discontinuation is commonly observed. With the aim of overcoming these limitations of OIT, several trials have studied omalizumab (anti-IgE monoclonal antibody) as an adjuvant treatment for patients undergoing OIT. Results from these trials have shown that the addition of omalizumab to OIT leads to a significant decrease in the frequency and severity of reactions, which allows for an increase in the threshold of tolerance to food allergens. This review provides a summary of the current literature and addresses some of the key questions that remain regarding the use of omalizumab in conjunction with OIT.

View details for PubMedID 28782296
A new fluorescent-avidin-based method for quantifying basophil activation in whole blood JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Mukai, K., Chinthrajah, R., Nadeau, K. C., Tsai, M., Gaudenzio, N., Galli, S. J. 2017; 140 (4): 1202-+
View details for PubMedID 28606590

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Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Frischmeyer-Guerrerio, P. A., Masilamani, M., Gu, W., Brittain, E., Wood, R., Kim, J., Nadeau, K., Jarvinen, K. M., Grishin, A., Lindblad, R., Sampson, H. A. 2017; 140 (4): 1043-+
Abstract

In our recent clinical trial, the addition of omalizumab to oral immunotherapy (OIT) for milk allergy improved safety, but no significant clinical benefit was detected.We sought to investigate mechanisms by which omalizumab modulates immunity in the context of OIT and to identify baseline biomarkers that predict subgroups of patients most likely to benefit from omalizumab.Blood was obtained at baseline and multiple time points during a placebo-controlled trial of OIT for milk allergy in which subjects were randomized to receive omalizumab or placebo. Immunologic outcomes included measurement of basophil CD63 expression and histamine release and casein-specific CD4+ regulatory T-cell proliferation. Biomarkers were analyzed in relationship to measurements of safety and efficacy.Milk-induced basophil CD63 expression was transiently reduced in whole blood samples from both omalizumab- and placebo-treated subjects. However, IgE-dependent histamine release increased in washed cell preparations from omalizumab- but not placebo-treated subjects. No increase in regulatory T-cell frequency was evident in either group. Subjects with lower rates of adverse reactions, regardless of arm, experienced better clinical outcomes. Pre-OIT basophil reactivity positively associated with occurrence of symptoms during OIT, whereas the baseline milk IgE/total IgE ratio correlated with the likelihood of achieving sustained unresponsiveness. A�combination of baseline basophil and serologic biomarkers defined a subset of patients in which adjunctive therapy with omalizumab was associated with attainment of sustained unresponsiveness and a reduction in adverse reactions.Combining omalizumab therapy with milk OIT led to distinct alterations in basophil reactivity but not T-cell responses. Baseline biomarkers can identify subjects most likely to benefit from adjunctive therapy with omalizumab.

View details for DOI 10.1016/j.jaci.2017.03.028

View details for Web of Science ID 000412172900016

View details for PubMedID 28414061

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Allergen immunotherapy for IgE-mediated food allergy: protocol for a systematic review (vol 6, 24, 2016) CLINICAL AND TRANSLATIONAL ALLERGY Dhami, S., Nurmatov, U., Pajno, G., Fernandez-Rivas, M., Muraro, A., Roberts, G., Akdis, C., Alvaro-Lozano, M., Beyer, K., Bindslev-Jensen, C., Burks, W., du Toit, G., Ebisawa, M., Eigenmann, P., Knol, E., Makela, M., Nadeau, K., O'Mahony, L., Papadopoulos, N., Poulsen, L., Sackesen, C., Sampson, H., Santos, A., van Ree, R., Timmermans, F., Sheikh, A. 2017; 7: 31
Abstract

[This corrects the article DOI: 10.1186/s13601-016-0113-z.].

View details for DOI 10.1186/s13601-017-0166-7

View details for Web of Science ID 000411014200003

View details for PubMedID 28932385

View details for PubMedCentralID PMC5602938
IL-4R alpha Inhibitor for Atopic Disease CELL Chang, H. Y., Nadeau, K. C. 2017; 170 (2): 222
Abstract

Dupilumab is a fully human IgG4 monoclonal antibody directed against the IL-4R? subunit of IL-4 and IL-13 receptors. It blocks the signaling pathways of IL-4 and IL-13, key cytokines that drive type 2 inflammatory response. In March 2017, dupilumab was approved for use in the treatment of atopic dermatitis (eczema). To view this Bench to Bedside, open or download the PDF.

View details for PubMedID 28708993
Cord blood T cell subpopulations and associations with maternal cadmium and arsenic exposures PLOS ONE Nygaard, U. C., Li, Z., Palys, T., Jackson, B., Subbiah, M., Malipatlolla, M., Sampath, V., Maecker, H., Karagas, M. R., Nadeau, K. C. 2017; 12 (6): e0179606
Abstract

Arsenic and cadmium are environmental pollutants, and although the evidence for adverse immune effects after prenatal arsenic and cadmium exposures is increasing, little is known about the underlying immunological mechanisms.We investigated the relationship between prenatal arsenic and cadmium exposures and a variety of T cell subpopulations measured in cord blood for 63 participants in the New Hampshire Birth Cohort Study. Post-partum toenail concentrations of arsenic and cadmium were used as an estimate of maternal exposure during pregnancy. The characteristics of cord blood proportions of T lymphocytes and subpopulations (expression of markers for Th1, Th2, Th17, Th1Th17, induced and natural regulatory T cells and NKTs) are presented.In regression analyses, maternal arsenic exposure levels were inversely associated with cord blood T helper memory cells (-21%, 95% CI: -36%, -3%) and the association was found to be stronger in females. They were also inversely associated with activated T helper memory cells, particularly in males (-26%, 95% CI: -43%, -3%). Similarly, inverse associations were observed between cadmium exposure levels and activated T helper memory cells (-16%, 95% CI: -30%, -1%) and also for T helper memory cells in females (-20%, 95% CI: -35%, -3%).The results suggest that prenatal exposures to relatively low levels of arsenic and cadmium may contribute to altered distribution of T cell populations at birth. These changes in theory, could have contributed to the previously reported immunosuppressive effects observed later in infancy/childhood.

View details for PubMedID 28662050
Biologic Therapies for Immunoglobulin E-mediated Food Allergy and Eosinophilic Esophagitis IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA Otani, I. M., Nadeau, K. C. 2017; 37 (2): 369-?
Abstract

Immunoglobulin (Ig) E-mediated food allergy and eosinophilic esophagitis (EoE) are chronic, allergen-mediated disorders characterized by an aberrant TH2 immune response. The development and investigation of biologics for the treatment of IgE-mediated food allergy and eosinophilic esophagitis have provided further insight into the pathophysiology and management of these disorders. This article provides an overview of biologic therapies that are being investigated or have potential as treatments for IgE-mediated food allergy and eosinophilic esophagitis. Identification of EoE phenotypes that are responsive to biologics and investigation of biologics combined with other therapies may help elucidate a role for biologics in EoE.

View details for DOI 10.1016/j.iac.2017.01.010

View details for Web of Science ID 000400321000013

View details for PubMedID 28366483
Traffic-Related Air Pollution and Telomere Length in Children and Adolescents Living in Fresno, CA: A Pilot Study. Journal of occupational and environmental medicine Lee, E. Y., Lin, J., Noth, E. M., Hammond, S. K., Nadeau, K. C., Eisen, E. A., Balmes, J. R. 2017; 59 (5): 446-452
Abstract

The main objective of this pilot study was to gather preliminary information about how telomere length (TL) varies in relation to exposure to polycyclic aromatic hydrocarbons (PAHs) in children living in a highly polluted city.We conducted a cross-sectional study of children living in Fresno, California (n?=?14). Subjects with and without asthma were selected based on their annual average PAH level in the 12-months prior to their blood draw. We measured relative telomere length from peripheral blood mononuclear cells (PBMC).We found an inverse linear relationship between average PAH level and TL (R?=?0.69), as well as between age and TL (R?=?0.21). Asthmatics had shorter mean telomere length than non-asthmatics (TLasthmatic?=?1.13, TLnon-asthmatic?=?1.29).These preliminary findings suggest that exposure to ambient PAH may play a role in telomere shortening.Become familiar with previous evidence suggesting that telomere length may be a biomarker of air pollution-induced cytotoxicity.Summarize the new findings on the association between polycyclic aromatic hydrocarbon (PAH) exposure and telomere length in adolescents, including those with asthma.Discuss the implications for recommendations and policies to mitigate the health and respiratory effects of traffic-related air pollution.

View details for DOI 10.1097/JOM.0000000000000996

View details for PubMedID 28486341
Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children's Environmental Health Studies: The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group ENVIRONMENTAL HEALTH PERSPECTIVES Breton, C. V., Marsit, C. J., Faustman, E., Nadeau, K., Goodrich, J. M., Dolinoy, D. C., Herbstman, J., Holland, N., LaSalle, J. M., Schmidt, R., Yousefi, P., Perera, F., Joubert, B. R., Wiemels, J., Taylor, M., Yang, I. V., Chen, R., Hew, K. M., Freeland, D. M., Miller, R., Murphy, S. K. 2017; 125 (4): 511-526
Abstract

Characterization of the epigenome is a primary interest for children's environmental health researchers studying the environmental influences on human populations, particularly those studying the role of pregnancy and early-life exposures on later-in-life health outcomes.Our objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children's Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis.We address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research.A common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children's health.The dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli.

View details for DOI 10.1289/EHP595

View details for Web of Science ID 000397904400011

View details for PubMedID 28362264
Oral immunotherapy for food allergy SEMINARS IN IMMUNOLOGY Freeland, D., Manohar, M., Andorf, S., Hobson, B. D., Zhang, W., Nadeau, K. C. 2017; 30: 36?44
Abstract

Food allergy is a pathological, potentially deadly cascade of immune responses to molecules or molecular fragments that are normally innocuous when encountered in foods, such as milk, egg, or peanut. As the incidence and prevalence of food allergy rise, the standard of care is poised to advance beyond food allergen avoidance coupled with injectable epinephrine treatment of allergen-induced systemic reactions. Recent studies provide evidence that oral immunotherapy may effectively redirect the atopic immune responses of food allergy patients as they ingest small but gradually increasing allergen doses over many months, eliciting safer immune responses to these antigens. Research into the molecular and cellular bases of pathological and therapeutic immune responses, and into the possibilities for their safe and effective modulation, is generating tremendous interest in basic and clinical immunology. We synthesize developments, innovations, and key challenges in our understanding of the immune mechanisms associated with atopy and oral immunotherapy for food allergy.

View details for PubMedID 28865877

View details for PubMedCentralID PMC5776738
Association of Clinical Reactivity with Sensitization to Allergen Components in Multifood-Allergic Children. journal of allergy and clinical immunology. In practice Andorf, S., Borres, M. P., Block, W., Tupa, D., Bollyky, J. B., Sampath, V., Elizur, A., Lidholm, J., Jones, J. E., Galli, S. J., Chinthrajah, R. S., Nadeau, K. C. 2017
Abstract

Thirty percent of children with food allergies have multiple simultaneous allergies; however, the features of these multiple allergies are not well characterized serologically or clinically.We comprehensively evaluated 60 multifood-allergic patients by measuring serum IgE to key allergen components, evaluating clinical histories and medication use, performing skin tests, and conducting double-blind, placebo-controlled food challenges (DBPCFCs).Sixty participants with multiple food allergies were characterized by clinical history, DBPCFCs, total IgE, specific IgE, and component-resolved diagnostics (IgE and IgG4) data. The food allergens tested were almond, egg, milk, sesame, peanut, pecan, walnut, hazelnut, cashew, pistachio, soy, and wheat.Our data demonstrate that of the reactions observed during a graded DBPCFC, gastrointestinal reactions occurred more often in boys than in girls, as well as in individuals with high levels of IgE to 2S albumins from cashew, walnut, and hazelnut. Certain food allergies often occurred concomitantly in individuals (ie, cashew/pistachio and walnut/pecan/hazelnut). IgE testing to components further corroborated serological relationships between and among these clustered food allergies.Associations of certain food allergies were shown by DBPCFC outcomes as well as by correlations in IgE reactivity to structurally related food allergen components. Each of these criteria independently demonstrated a significant association between allergies to cashew and pistachio, as well as among allergies to walnut, pecan, and hazelnut.

View details for DOI 10.1016/j.jaip.2017.01.016

View details for PubMedID 28351786
Omalizumab facilitates rapid oral desensitization for peanut allergy. journal of allergy and clinical immunology MacGinnitie, A. J., Rachid, R., Gragg, H., Little, S. V., Lakin, P., Cianferoni, A., Heimall, J., Makhija, M., Robison, R., Chinthrajah, R. S., Lee, J., LeBovidge, J., Dominguez, T., Rooney, C., Lewis, M. O., Koss, J., Burke-Roberts, E., Chin, K., Logvinenko, T., Pongracic, J. A., Umetsu, D. T., Spergel, J., Nadeau, K. C., Schneider, L. C. 2017; 139 (3): 873-881 e8
Abstract

Peanut oral immunotherapy is a promising approach to peanut allergy, but reactions are frequent, and some patients cannot be desensitized. The anti-IgE medication omalizumab (Xolair; Genentech, South San Francisco, Calif) might allow more rapid peanut updosing and decrease reactions.We sought to evaluate whether omalizumab facilitated rapid peanut desensitization in highly allergic patients.Thirty-seven subjects were randomized to omalizumab (n�=�29) or placebo (n�=�8). After 12�weeks of treatment, subjects underwent a rapid 1-day desensitization of up to 250�mg of peanut protein, followed by weekly increases up to 2000�mg. Omalizumab was then discontinued, and subjects continued on 2000�mg of peanut protein. Subjects underwent an open challenge to 4000�mg of peanut protein 12�weeks after stopping study drug. If tolerated, subjects continued on 4000�mg of peanut protein daily.The median peanut dose tolerated on the initial desensitization day was 250�mg for omalizumab-treated subjects versus 22.5�mg for placebo-treated subject. Subsequently, 23 (79%) of 29 subjects randomized to omalizumab tolerated 2000�mg of peanut protein 6�weeks after stopping omalizumab versus 1 (12%) of 8 receiving placebo (P�<�.01). Twenty-three subjects receiving omalizumab versus 1 subject receiving placebo passed the 4000-mg food challenge. Overall reaction rates were not significantly lower in omalizumab-treated versus placebo-treated subjects (odds ratio, 0.57; P�=�.15), although omalizumab-treated subjects were exposed to much higher peanut doses.Omalizumab allows subjects with peanut allergy to be rapidly desensitized over as little as 8�weeks of peanut oral immunotherapy. In the majority of subjects, this desensitization is sustained after omalizumab is discontinued. Additional studies will help clarify which patients would benefit most from this approach.

View details for DOI 10.1016/j.jaci.2016.08.010

View details for PubMedID 27609658
Omalizumab facilitates rapid oral desensitization for peanut allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY MacGinnitie, A. J., Rachid, R., Gragg, H., Little, S. V., Lakin, P., Cianferoni, A., Heimall, J., Makhija, M., Robison, R., Chinthrajah, R. S., Lee, J., LeBovidge, J., Dominguez, T., Rooney, C., Lewis, M. O., Koss, J., Burke-Roberts, E., Chin, K., Logvinenko, T., Pongracic, J. A., Umetsu, D. T., Spergel, J., Nadeau, K. C., Schneider, L. C. 2017; 139 (3): 873-?
View details for DOI 10.1016/j.jaci.2016.08.010

View details for Web of Science ID 000397295800020
Preservation of epithelial cell barrier function and muted inflammation in resistance to allergic rhinoconjunctivitis from house dust mite challenge JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Ahuja, S. K., Manoharan, M. S., Harper, N. L., Jimenez, F., Hobson, B. D., Martinez, H., Ingale, P., Liu, Y., Carrillo, A., Lou, Z., Kellog, D. L., Ahuja, S. S., Rather, C. G., Esch, R. E., Ramirez, D. A., Clark, R. A., Nadeau, K., Andrews, C. P., Jacobs, R. L., He, W. 2017; 139 (3): 844-854
Abstract

An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis, relates to an intact epithelial/epidermal barrier during early childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen.The aim of this study was to obtain direct support of the epithelial/epidermal barrier model for allergic rhinoconjunctivitis.Twenty-three adults allergic to house dust mites (HDMs) (M+) and 15 nonsensitive, nonallergic (M-) participants completed 3-hour exposures to aerosolized HDM (Dermatophagoides pteronyssinus) powder on 4 consecutive days in an allergen challenge chamber. We analyzed: (1) peripheral blood leukocyte levels and immune responses; and (2) RNA sequencing-derived expression profiles of nasal cells, before and after HDM exposure.On HDM challenge: (1) only M+ persons developed allergic rhinoconjunctivitis symptoms; and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M- participants; gross differences in these parameters were not observed at baseline (pre-exposure). Two key differences were observed. First, peripheral blood CD4(+) and CD8(+) T-cell activation levels initially decreased in M- participants versus increased in M+ participants. Second, in M- compared with M+ participants, genes that promoted epidermal/epithelial barrier function (eg, filament-aggregating protein [filaggrin]) versus inflammation (eg, chemokines) and innate immunity (interferon) were upregulated versus muted, respectively.An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T-cell activation in the peripheral blood and inflammatory response in the nasal compartment, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function.

View details for DOI 10.1016/j.jaci.2016.08.019

View details for PubMedID 27658763
Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24 hours before analysis JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Mukai, K., Gaudenzio, N., Gupta, S., Vivanco, N., Bendall, S. C., Maecker, H. T., Chinthrajah, R. S., Tsai, M., Nadeau, K. C., Galli, S. J. 2017; 139 (3): 889-?
Abstract

Basophil activation tests (BATs) have promise for research and for clinical monitoring of patients with allergies. However, BAT protocols vary in blood anticoagulant used and temperature and time of storage before testing, complicating comparisons of results from various studies.We attempted to establish a BAT protocol that would permit analysis of blood within 24�hours of obtaining the sample.Blood from 46 healthy donors and 120 patients with peanut allergy was collected into EDTA or heparin tubes, and samples were stored at 4�C or room temperature for 4 or 24�hours before performing BATs.Stimulation with anti-IgE or IL-3 resulted in strong upregulation of basophil CD203c in samples collected in EDTA or heparin, stored at 4�C, and analyzed 24�hours after sample collection. However, a CD63(hi) population of basophils was not observed in any conditions in EDTA-treated samples unless exogenous calcium/magnesium was added at the time of anti-IgE stimulation. By contrast, blood samples collected in heparin tubes were adequate for quantification of upregulation of basophil CD203c and identification of a population of CD63(hi) basophils, irrespective of whether the specimens were analyzed by means of conventional flow cytometry or cytometry by time-of-flight mass spectrometry, and such tests could be performed after blood was stored for 24�hours at 4�C.BATs to measure upregulation of basophil CD203c and induction of a CD63(hi) basophil population can be conducted with blood obtained in heparin tubes and stored at 4�C for 24�hours.

View details for DOI 10.1016/j.jaci.2016.04.060

View details for Web of Science ID 000397295800022

View details for PubMedCentralID PMC5237629
Single-Cell Signatures Link Ambient Air Pollution to Remodeling of the Immune System in Asthmatics Fan-Minogue, H., Hew, K., Lyu, S., Nygaard, U., Lurmann, F., Noth, E., Balmes, J., Margolis, H., Hammond, K., Eisen, E., Miller, R., Nadeau, K. MOSBY-ELSEVIER. 2017: AB184
View details for DOI 10.1016/j.jaci.2016.12.600

View details for Web of Science ID 000401699800486
Analysis of Peanut-specific T Cells as a Tool to Monitor State of Disease Schulten, V., Oseroff, C., Tripple, V., Nadeau, K. C., Manohar, M., Sette, A., Peters, B. MOSBY-ELSEVIER. 2017: AB72
View details for DOI 10.1016/j.jaci.2016.12.281

View details for Web of Science ID 000401699800130
Assessing basophil activation by flow cytometry and mass cytometry in blood stored 24 hours before analysis Mukai, K., Gaudenzio, N., Gupta, S., Vivanco, N., Bendall, S. C., Maecker, H. T., Chinthrajah, R., Tsai, M., Nadeau, K. C., Galli, S. J. MOSBY-ELSEVIER. 2017: AB124
View details for DOI 10.1016/j.jaci.2016.12.402

View details for Web of Science ID 000401699800293
Immune Differences in Asthmatic Children Using Mass Cytometry Paglino, T., Prunicki, M., Zhou, X., Nadeau, K. C. MOSBY-ELSEVIER. 2017: AB375
View details for DOI 10.1016/j.jaci.2016.12.897

View details for Web of Science ID 000401699800774
Randomized Placebo-Controlled Multicenter Clinical Trial of Wheat Oral Immunotherapy Nowak-Wegrzyn, A. H., Wood, R. A., Nadeau, K. C., Pongracic, J. A., Henning, A., Beyer, K., Lindblad, R. W., Sampson, H. A. MOSBY-ELSEVIER. 2017: AB378
View details for DOI 10.1016/j.jaci.2016.12.904

View details for Web of Science ID 000401699800781
Fraction of Exhaled Nitric Oxide (FeNO) As A Predictor Of GI Symptoms During Food Allergen Updosing Chollet, M. B., Nadeau, K. C., Purington, N., Desai, M., Chinthrajah, R. MOSBY-ELSEVIER. 2017: AB258
View details for DOI 10.1016/j.jaci.2016.12.830

View details for Web of Science ID 000401699800709
Characterization of multifood allergic children based on clinical and serological data Andorf, S., Borres, M., Block, W., Lidholm, J., Jones, J. E., Galli, S. J., Chinthrajah, R., Nadeau, K. C. MOSBY-ELSEVIER. 2017: AB140
View details for DOI 10.1016/j.jaci.2016.12.460

View details for Web of Science ID 000401699800349
Quality of Life, Risk Perception, and Treatment Burden with Peanut Oral Immunotherapy LeBovidge, J. S., Rachid, R. A., MacGinnitie, A., Secor, W., Burke-Roberts, E. S., Pongracic, J. A., Spergel, J. M., Nadeau, K., Umetsu, D. T., Schneider, L. C. MOSBY-ELSEVIER. 2017: AB133
View details for DOI 10.1016/j.jaci.2016.12.438

View details for Web of Science ID 000401699800328
Peanut Specific-CD4+T Cells Responses in Peanut Allergic and Peanut Sensitized but Tolerant Subjects Kwok, W. W., Farrington, M. L., Whalen, E., Wambre, E. R., Nadeau, K., Renand, A. MOSBY-ELSEVIER. 2017: AB71
View details for DOI 10.1016/j.jaci.2016.12.279

View details for Web of Science ID 000401699800128
Efficacy and Safety of Long-Term Epicutaneous Immunotherapy (EPIT) Treatment of Peanut Allergy with Viaskin (R) peanut: Results of the Two-Year Extension of the Vipes Phase IIb Clinical Trial Shreffler, W. G., Nadeau, K. C., Leonard, S. A., Sussman, G. L., Sampson, H. A. MOSBY-ELSEVIER. 2017: AB377
View details for DOI 10.1016/j.jaci.2016.12.901

View details for Web of Science ID 000401699800778
Purification and Characterization of a Black Walnut (Juglans nigra) Allergen, Jug n 4 JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY Zhang, Y., Du, W., Fan, Y., Yi, J., Lyu, S., Nadeau, K. C., Thomas, A. L., McHugh, T. 2017; 65 (2): 454-462
Abstract

Tree nuts as a group cause a significant number of fatal anaphylactic reactions to foods. Walnuts (Juglans spp.) were one of the leading causes of allergic reactions to tree nuts in the US and Japan. The purpose of this study was to purify and characterize potential food allergens from black walnut. Here, we report the isolation of the black walnuts allergen Jug n 4 (an 11S globulin) by ammonium sulfate precipitation, and hydrophobic interaction and size exclusion chromatography. Reducing SDS-PAGE analysis indicated that purified Jug n 4 consists of 3 major bands. N-terminal sequencing data of these bands indicated that they were the results of a post-transcriptional protease cleavage of the mature protein at a site that consists of a known conserved protease recognition motif, NGXEET. Western blot experiments revealed that 32% of the sera from 25 patients with double-blind, placebo-controlled clinical walnut allergy contained IgE antibodies that recognized Jug n 4, indicating that it is a walnut allergen. Identifying this and additional allergens may facilitate the understanding of the allergenicity of seed storage proteins in tree nuts and their cross-reactivity.

View details for DOI 10.1021/acs.jafc.6b04387

View details for PubMedID 27936684
Allergen immunotherapy for IgE-mediated food allergy: a systematic review and meta-analysis. Allergy Nurmatov, U., Dhami, S., Arasi, S., Pajno, G. B., Fernandez-Rivas, M., Muraro, A., Roberts, G., Akdis, C., Alvaro-Lozano, M., Beyer, K., Bindslev-Jensen, C., Burks, W., Du Toit, G., Ebisawa, M., Eigenmann, P., Knol, E., Makela, M., Nadeau, K. C., O'mahony, L., Papadopoulos, N., Poulsen, L. K., Sackesen, C., Sampson, H., Santos, A., van Ree, R., Timmermans, F., Sheikh, A. 2017
Abstract

The European Academy of Allergy and Clinical Immunology (EAACI) is developing Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated Food Allergy. To inform the development of clinical recommendations, we sought to critically assess evidence on the effectiveness, safety and cost-effectiveness of AIT in the management of food allergy.We undertook a systematic review and meta-analysis that involved searching nine international electronic databases for randomized controlled trials (RCTs) and nonrandomized studies (NRS). Eligible studies were independently assessed by two reviewers against predefined eligibility criteria. The quality of studies was assessed using the Cochrane Risk of Bias tool for RCTs and the Cochrane ACROBAT-NRS tool for quasi-RCTs. Random-effects meta-analyses were undertaken, with planned subgroup and sensitivity analyses.We identified 1814 potentially relevant papers from which we selected 31 eligible studies, comprising of 25 RCTs and six NRS, studying a total of 1259 patients. Twenty-five trials evaluated oral immunotherapy (OIT), five studies investigated sublingual immunotherapy, and one study evaluated epicutaneous immunotherapy. The majority of these studies were in children. Twenty-seven studies assessed desensitization, and nine studies investigated sustained unresponsiveness postdiscontinuation of AIT. Meta-analyses demonstrated a substantial benefit in terms of desensitization (risk ratio (RR)�=�0.16, 95% CI 0.10, 0.26) and suggested, but did not confirm sustained unresponsiveness (RR�=�0.29, 95% CI 0.08, 1.13). Only one study reported on disease-specific quality of life (QoL), which reported no comparative results between OIT and control group. Meta-analyses revealed that the risk of experiencing a systemic adverse reaction was higher in those receiving AIT, with a more marked increase in the risk of local adverse reactions. Sensitivity analysis excluding those studies judged to be at high risk of bias demonstrated the robustness of summary estimates of effectiveness and safety of AIT for food allergy. None of the studies reported data on health economic analyses.AIT may be effective in raising the threshold of reactivity to a range of foods in children with IgE-mediated food allergy whilst receiving (i.e. desensitization) and post-discontinuation of AIT. It is, however, associated with a modest increased risk in serious systemic adverse reactions and a substantial increase in minor local adverse reactions. More data are needed in relation to adults, long term effects, the impact on QoL and the cost-effectiveness of AIT.

View details for DOI 10.1111/all.13124

View details for PubMedID 28058751
Modified High-Molecular-Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Gebe, J. A., Yadava, K., Ruppert, S. M., Marshall, P., Hill, P., Falk, B. A., Sweere, J. M., Han, H., Kaber, G., Medina, C., Mikecz, K., Ziegler, S. F., Balaji, S., Keswani, S. G., Perez, V. A., Butte, M. J., Nadeau, K., Altemeier, W. A., Fanger, N., Bollyky, P. L. 2017; 56 (1): 109-120
Abstract

The extracellular matrix in asthmatic lungs contains abundant low-molecular-weight hyaluronan, and this is known to promote antigen presentation and allergic responses. Conversely, high-molecular-weight hyaluronan (HMW-HA), typical of uninflamed tissues, is known to suppress inflammation. We investigated whether HMW-HA can be adapted to promote tolerance to airway allergens. HMW-HA was thiolated to prevent its catabolism and was tethered to allergens via thiol linkages. This platform, which we call "XHA," delivers antigenic payloads in the context of antiinflammatory costimulation. Allergen/XHA was administered intranasally to mice that had been sensitized previously to these allergens. XHA prevents allergic airway inflammation in mice sensitized previously to either ovalbumin or cockroach proteins. Allergen/XHA treatment reduced inflammatory cell counts, airway hyperresponsiveness, allergen-specific IgE, and T helper type 2 cell cytokine production in comparison with allergen alone. These effects were allergen specific and IL-10 dependent. They were durable for weeks after the last challenge, providing a substantial advantage over the current desensitization protocols. Mechanistically, XHA promoted CD44-dependent inhibition of nuclear factor-?B signaling, diminished dendritic cell maturation, and reduced the induction of allergen-specific CD4 T-helper responses. XHA and other potential strategies that target CD44 are promising alternatives for the treatment of asthma and allergic sinusitis.

View details for DOI 10.1165/rcmb.2016-0111OC

View details for Web of Science ID 000392133000012

View details for PubMedCentralID PMC5248962
Immune monitoring for precision medicine in allergy and asthma. Current opinion in immunology Boyd, S. D., Hoh, R. A., Nadeau, K. C., Galli, S. J. 2017; 48: 82?91
Abstract

'Precision Medicine' embodies the analyses of extensive data collected from patients and their environments to identify and apply patient-specific prophylactic strategies and medical treatments to improve clinical outcomes and healthcare cost-effectiveness. Many new methods have been developed for evaluating the activity of the human immune system. Such 'immune monitoring' approaches are now being used in studies of allergy and asthma in the hope of identifying better correlates of disease status, predictors of therapeutic outcomes, and potential side-effects of treatment. Together with analyses of family histories, genetic and other biometric data, and measurements of exposures to environmental and other risk factors for developing or exacerbating disease, immune monitoring approaches promise to enable 'Precision Medicine' for allergic diseases and asthma.

View details for DOI 10.1016/j.coi.2017.08.007

View details for PubMedID 28889067

View details for PubMedCentralID PMC5743231
Effectiveness of air purifier on health outcomes and indoor particles in homes of children with allergic diseases in Fresno, California: A pilot study JOURNAL OF ASTHMA Park, H., Cheng, K., Tetteh, A. O., Hildemann, L. M., Nadeau, K. C. 2017; 54 (4): 341-346
Abstract

Epidemiologic studies indicate that indoor air pollution is correlated with morbidity caused by allergic diseases. We evaluated the effectiveness of reducing the levels of indoor fine particulate matter <2.5�micrometer diameter (PM2.5) in Fresno, California using air purifiers on health outcomes in children with asthma and/or allergic rhinitis.The active group (with air purifiers) and the control group consisted of eight houses each. Air purifiers were installed in the living rooms and bedrooms of the subjects in the active group during the entire 12-week study duration. Childhood asthma control test, peak flow rate monitoring, and nasal symptom scores were evaluated at weeks 0, 6, and 12.At 12�weeks, the active group showed a trend toward an improvement of childhood asthma control test scores and mean evening peak flow rates, whereas the control group showed deterioration in the same measures. Total and daytime nasal symptoms scores significantly reduced in the active group (p = 0.001 and p = 0.011, respectively). The average indoor PM2.5 concentrations reduced by 43% (7.42 to 4.28�?g/m(3)) in the active group (p = 0.001).Intervention with air purifiers reduces indoor PM2.5 levels with significant improvements in nasal symptoms in children with allergic rhinitis in Fresno.

View details for DOI 10.1080/02770903.2016.1218011

View details for Web of Science ID 000400169700002
Deciphering the black box of food allergy mechanisms. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology Sampath, V., Tupa, D., Graham, M. T., Chatila, T. A., Spergel, J. M., Nadeau, K. C. 2017; 118 (1): 21-27
Abstract

To review our current understanding of immunotherapy, the immune mechanisms underlying food allergy, and the methodological advances that are furthering our understanding of the role of immune cells and other molecules in mediating food allergies.Literature searches were performed using the following combination of terms: allergy, immunotherapy, food, and mechanisms. Data from randomized clinical studies using state-of-the-art mechanistic tools were prioritized.Articles were selected based on their relevance to food allergy.Current standard of care for food allergies is avoidance of allergenic foods and the use of epinephrine in case of severe reaction during unintentional ingestion. During the last few decades, great strides have been made in understanding the cellular and molecular mechanisms underlying food allergy, and this information is spearheading the development of exciting new treatments.Immunotherapy protocols are effective in desensitizing individuals to specific allergens; however, recurrence of allergic sensitization is common after discontinuation of therapy. Interestingly, in a subset of individuals, immunotherapy is protective against allergens even after discontinuation of immunotherapy. Whether this protection is permanent is currently unknown because of inadequate long-term follow-up data. Research on understanding the underlying mechanisms may assist in modifying protocols to improve outcome and enable sustained unresponsiveness, rather than a temporary relief against food allergies. The cellular changes brought about by immunotherapy are still a black box, but major strides in our understanding are being made at an exciting pace.

View details for DOI 10.1016/j.anai.2016.10.017

View details for PubMedID 28007085

View details for PubMedCentralID PMC5193239
Food allergy: immune mechanisms, diagnosis and immunotherapy NATURE REVIEWS IMMUNOLOGY Yu, W., Freeland, D. M., Nadeau, K. C. 2016; 16 (12): 751-765
Abstract

Food allergy is a pathological, potentially deadly, immune reaction triggered by normally innocuous food protein antigens. The prevalence of food allergies is rising and the standard of care is not optimal, consisting of food-allergen avoidance and treatment of allergen-induced systemic reactions with adrenaline. Thus, accurate diagnosis, prevention and treatment are pressing needs, research into which has been catalysed by technological advances that are enabling a mechanistic understanding of food allergy at the cellular and molecular levels. We discuss the diagnosis and treatment of IgE-mediated food allergy in the context of the immune mechanisms associated with healthy tolerance to common foods, the inflammatory response underlying most food allergies, and immunotherapy-induced desensitization. We highlight promising research advances, therapeutic innovations and the challenges that remain.

View details for DOI 10.1038/nri.2016.111

View details for Web of Science ID 000389134500010

View details for PubMedID 27795547

View details for PubMedCentralID PMC5123910
Identification, characterization, and initial epitope mapping of pine nut allergen Pin k 2 FOOD RESEARCH INTERNATIONAL Zhang, Y., Du, W., Fan, Y., Yi, J., Lyu, S., Nadeau, K. C., McHugh, T. H. 2016; 90: 268-274
View details for DOI 10.1016/j.foodres.2016.10.043

View details for Web of Science ID 000390636700029
Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. journal of clinical investigation Walter, J. E., Rosen, L. B., Csomos, K., Rosenberg, J. M., Mathew, D., Keszei, M., Ujhazi, B., Chen, K., Lee, Y. N., Tirosh, I., Dobbs, K., Al-Herz, W., Cowan, M. J., Puck, J., Bleesing, J. J., Grimley, M. S., Malech, H., De Ravin, S. S., Gennery, A. R., Abraham, R. S., Joshi, A. Y., Boyce, T. G., Butte, M. J., Nadeau, K. C., Balboni, I., Sullivan, K. E., Akhter, J., Adeli, M., El-Feky, R. A., El-Ghoneimy, D. H., Dbaibo, G., Wakim, R., Azzari, C., Palma, P., Cancrini, C., Capuder, K., Condino-Neto, A., Costa-Carvalho, B. T., Oliveira, J. B., Roifman, C., Buchbinder, D., Kumanovics, A., Franco, J. L., Niehues, T., Schuetz, C., Kuijpers, T., Yee, C., Chou, J., Masaad, M. J., Geha, R., Uzel, G., Gelman, R., Holland, S. M., Recher, M., Utz, P. J., Browne, S. K., Notarangelo, L. D. 2016; 126 (11): 4389-?
View details for DOI 10.1172/JCI91162

View details for PubMedID 27801680

View details for PubMedCentralID PMC5096894
Epigenetic Changes During Food-Specific Immunotherapy. Current allergy and asthma reports Bunning, B. J., DeKruyff, R. H., Nadeau, K. C. 2016; 16 (12): 87-?
Abstract

The prevalence and severity of IgE-mediated food allergy has increased dramatically over the last 15�years and is becoming a global health problem. Multiple lines of evidence suggest that epigenetic modifications of the genome resulting from gene-environment interactions have a key role in the increased prevalence of atopic disease. In this review, we describe the recent evidence suggesting how epigenetic changes mediate susceptibility to food allergies, and discuss how immunotherapy (IT) may reverse these effects. We discuss the areas of the epigenome as yet unexplored in terms of food allergy and IT such as histone modification and chromatin accessibility, and new techniques that may be utilized in future studies.Recent findings provide strong evidence that DNA methylation of certain promoter regions such as Forkhead box protein 3 is associated with clinical reactivity, and further, can be changed during IT treatment. Reports on other epigenetic changes are limited but also show evidence of significant change based on both disease status and treatment. In comparison to epigenetic studies focusing on asthma and allergic rhinitis, food allergy remains understudied. However, within the next decade, it is likely that epigenetic modifications may be used as biomarkers to aid in diagnosis and treatment of food-allergic patients. DNA methylation at specific loci has shown associations between food challenge outcomes, successful desensitization treatment, and overall phenotype compared to healthy controls.

View details for PubMedID 27943047
Effectiveness of air purifier on health outcomes and indoor particles in homes of children with allergic diseases in Fresno, California: A pilot study. journal of asthma Park, H., Cheng, K., Tetteh, A. O., Hildemann, L. M., Nadeau, K. C. 2016: 1-6
Abstract

Epidemiologic studies indicate that indoor air pollution is correlated with morbidity caused by allergic diseases. We evaluated the effectiveness of reducing the levels of indoor fine particulate matter <2.5�micrometer diameter (PM2.5) in Fresno, California using air purifiers on health outcomes in children with asthma and/or allergic rhinitis.The active group (with air purifiers) and the control group consisted of eight houses each. Air purifiers were installed in the living rooms and bedrooms of the subjects in the active group during the entire 12-week study duration. Childhood asthma control test, peak flow rate monitoring, and nasal symptom scores were evaluated at weeks 0, 6, and 12.At 12�weeks, the active group showed a trend toward an improvement of childhood asthma control test scores and mean evening peak flow rates, whereas the control group showed deterioration in the same measures. Total and daytime nasal symptoms scores significantly reduced in the active group (p = 0.001 and p = 0.011, respectively). The average indoor PM2.5 concentrations reduced by 43% (7.42 to 4.28�?g/m(3)) in the active group (p = 0.001).Intervention with air purifiers reduces indoor PM2.5 levels with significant improvements in nasal symptoms in children with allergic rhinitis in Fresno.

View details for PubMedID 27723364
Advances in food allergy oral immunotherapy: toward tolerance. Current opinion in immunology Hussey Freeland, D. M., Fan-Minogue, H., Spergel, J. M., Chatila, T. A., Nadeau, K. C. 2016; 42: 119-123
Abstract

The incidence of food allergy, a disease characterized by adverse immune responses that can render common foods life-threatening, is rising. Yet our current standard of care is simply avoidance of allergenic foods and administration of emergency medications upon accidental exposure. Significant advances have been made in food allergy oral immunotherapy, which is emerging as a potential preventive and curative treatment for this disease. The fundamental strategy of oral immunotherapy is to mitigate adverse immune responses to allergenic food proteins through repeated exposure; reduced reactivity to food allergens (desensitization) often results, but the establishment of sustained immune unresponsiveness or of permanent resolution (tolerance) is not certain. This review examines exciting recent developments in oral immunotherapy for food allergy.

View details for DOI 10.1016/j.coi.2016.08.002

View details for PubMedID 27745972
Advances in food allergy oral immunotherapy: toward tolerance CURRENT OPINION IN IMMUNOLOGY Freeland, D. M., Fan-Minogue, H., Spergel, J. M., Chatila, T. A., Nadeau, K. C. 2016; 42: 119-123
Abstract

The incidence of food allergy, a disease characterized by adverse immune responses that can render common foods life-threatening, is rising. Yet our current standard of care is simply avoidance of allergenic foods and administration of emergency medications upon accidental exposure. Significant advances have been made in food allergy oral immunotherapy, which is emerging as a potential preventive and curative treatment for this disease. The fundamental strategy of oral immunotherapy is to mitigate adverse immune responses to allergenic food proteins through repeated exposure; reduced reactivity to food allergens (desensitization) often results, but the establishment of sustained immune unresponsiveness or of permanent resolution (tolerance) is not certain. This review examines exciting recent developments in oral immunotherapy for food allergy.

View details for DOI 10.1016/j.coi.2016.08.002

View details for Web of Science ID 000387524300019
Temporal Regulation by Innate Type 2 Cytokines in Food Allergies. Current allergy and asthma reports Graham, M. T., Andorf, S., Spergel, J. M., Chatila, T. A., Nadeau, K. C. 2016; 16 (10): 75-?
Abstract

Food allergies (FAs) are a growing epidemic in western countries with poorly defined etiology. Defined as an adverse immune response to common food allergens, FAs present heterogeneously as a single- or multi-organ response that ranges in severity from localized hives and angioedema to systemic anaphylaxis.Current research focusing on epithelial-derived cytokines contends that temporal regulation by these factors impact initial sensitization and persistence of FA responses upon repeated food allergen exposure. Mechanistic understanding of FA draws insight from a myriad of atopic conditions studied in humans and modeled in mice. In this review, we will highlight how epithelial-derived cytokines initiate and then potentiate FAs. We will also review existing evidence of the contribution of other atopic diseases to FA pathogenesis and whether FA symptoms overlap with other atopic diseases.

View details for PubMedID 27771884
Modified High Molecular Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance. American journal of respiratory cell and molecular biology Gebe, J. A., Yadava, K., Ruppert, S. M., Marshall, P., Hill, P., Falk, B. A., Sweere, J. M., Han, H., Kaber, G., Medina, C., Mikecz, K., Ziegler, S. F., Balaji, S., Keswani, S. G., de Jesus Perez, V. A., Butte, M. J., Nadeau, K., Altemeier, W. A., Fanger, N., Bollyky, P. L. 2016: -?
Abstract

The extracellular matrix in asthmatic lungs contains abundant low-molecular-weight hyaluronan, and this is known to promote antigen presentation and allergic responses. Conversely, high-molecular-weight hyaluronan (HMW-HA), typical of uninflamed tissues, is known to suppress inflammation. We investigated whether HMW-HA can be adapted to promote tolerance to airway allergens. HMW-HA was thiolated to prevent its catabolism and was tethered to allergens via thiol linkages. This platform, which we call "XHA," delivers antigenic payloads in the context of antiinflammatory costimulation. Allergen/XHA was administered intranasally to mice that had been sensitized previously to these allergens. XHA prevents allergic airway inflammation in mice sensitized previously to either ovalbumin or cockroach proteins. Allergen/XHA treatment reduced inflammatory cell counts, airway hyperresponsiveness, allergen-specific IgE, and T helper type 2 cell cytokine production in comparison with allergen alone. These effects were allergen specific and IL-10 dependent. They were durable for weeks after the last challenge, providing a substantial advantage over the current desensitization protocols. Mechanistically, XHA promoted CD44-dependent inhibition of nuclear factor-?B signaling, diminished dendritic cell maturation, and reduced the induction of allergen-specific CD4 T-helper responses. XHA and other potential strategies that target CD44 are promising alternatives for the treatment of asthma and allergic sinusitis.

View details for PubMedID 27598620
Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24�hours before analysis. journal of allergy and clinical immunology Mukai, K., Gaudenzio, N., Gupta, S., Vivanco, N., Bendall, S. C., Maecker, H. T., Chinthrajah, R. S., Tsai, M., Nadeau, K. C., Galli, S. J. 2016
Abstract

Basophil activation tests (BATs) have promise for research and for clinical monitoring of patients with allergies. However, BAT protocols vary in blood anticoagulant used and temperature and time of storage before testing, complicating comparisons of results from various studies.We attempted to establish a BAT protocol that would permit analysis of blood within 24�hours of obtaining the sample.Blood from 46 healthy donors and 120 patients with peanut allergy was collected into EDTA or heparin tubes, and samples were stored at 4�C or room temperature for 4 or 24�hours before performing BATs.Stimulation with anti-IgE or IL-3 resulted in strong upregulation of basophil CD203c in samples collected in EDTA or heparin, stored at 4�C, and analyzed 24�hours after sample collection. However, a CD63(hi) population of basophils was not observed in any conditions in EDTA-treated samples unless exogenous calcium/magnesium was added at the time of anti-IgE stimulation. By contrast, blood samples collected in heparin tubes were adequate for quantification of upregulation of basophil CD203c and identification of a population of CD63(hi) basophils, irrespective of whether the specimens were analyzed by means of conventional flow cytometry or cytometry by time-of-flight mass spectrometry, and such tests could be performed after blood was stored for 24�hours at 4�C.BATs to measure upregulation of basophil CD203c and induction of a CD63(hi) basophil population can be conducted with blood obtained in heparin tubes and stored at 4�C for 24�hours.

View details for DOI 10.1016/j.jaci.2016.04.060

View details for PubMedID 27527263

View details for PubMedCentralID PMC5237629
Giant magnetoresistive sensor array for sensitive and specific multiplexed food allergen detection BIOSENSORS & BIOELECTRONICS Ng, E., Nadeau, K. C., Wang, S. X. 2016; 80: 359-365
Abstract

Current common allergen detection methods, including enzyme-linked immunosorbent assays (ELISAs) and dip-stick methods, do not provide adequate levels of sensitivity and specificity for at-risk allergic patients. A method for performing highly sensitive and specific detection of multiple food allergens is thus imperative as food allergies are becoming increasingly recognized as a major healthcare concern, affecting an estimated 4% of the total population. We demonstrate first instance of sensitive and specific multiplexed detection of major peanut allergens Ara h 1 and Ara h 2, and wheat allergen Gliadin using giant magnetoresistive (GMR) sensor arrays. Commercialized ELISA kits for Ara h 1 and Ara h 2 report limits of detection (LODs) at 31.5 ng/mL and 0.2 ng/mL, respectively. In addition, the 96-well-based ELISA developed in-house for Gliadin was found to have a LOD of 40 ng/mL. Our multiplexed GMR-based assay demonstrates the ability to perform all three assays on the same chip specifically and with sensitivities at LODs about an order of magnitude lower than those of 96-well-based ELISAs. LODs of GMR-based assays developed for Ara h 1, Ara h 2, and Gliadin were 7.0 ng/mL, 0.2 ng/mL, and 1.5 ng/mL, respectively, with little to no cross-reactivity. These LODs are clinically important as some patients could react strongly against such low allergen levels. Given the limitations of current industrial detection technology, multiplexed GMR-based assays provide a method for highly sensitive and specific simultaneous detection of any combination of food-product allergens, thus protecting allergic patients from life-threatening events, including anaphylaxis, by unintentional consumption.

View details for DOI 10.1016/j.bios.2016.02.002

View details for Web of Science ID 000372558500051
Giant magnetoresistive sensor array for sensitive and specific multiplexed food allergen detection. Biosensors & bioelectronics Ng, E., Nadeau, K. C., Wang, S. X. 2016; 80: 359-365
Abstract

Current common allergen detection methods, including enzyme-linked immunosorbent assays (ELISAs) and dip-stick methods, do not provide adequate levels of sensitivity and specificity for at-risk allergic patients. A method for performing highly sensitive and specific detection of multiple food allergens is thus imperative as food allergies are becoming increasingly recognized as a major healthcare concern, affecting an estimated 4% of the total population. We demonstrate first instance of sensitive and specific multiplexed detection of major peanut allergens Ara h 1 and Ara h 2, and wheat allergen Gliadin using giant magnetoresistive (GMR) sensor arrays. Commercialized ELISA kits for Ara h 1 and Ara h 2 report limits of detection (LODs) at 31.5 ng/mL and 0.2 ng/mL, respectively. In addition, the 96-well-based ELISA developed in-house for Gliadin was found to have a LOD of 40 ng/mL. Our multiplexed GMR-based assay demonstrates the ability to perform all three assays on the same chip specifically and with sensitivities at LODs about an order of magnitude lower than those of 96-well-based ELISAs. LODs of GMR-based assays developed for Ara h 1, Ara h 2, and Gliadin were 7.0 ng/mL, 0.2 ng/mL, and 1.5 ng/mL, respectively, with little to no cross-reactivity. These LODs are clinically important as some patients could react strongly against such low allergen levels. Given the limitations of current industrial detection technology, multiplexed GMR-based assays provide a method for highly sensitive and specific simultaneous detection of any combination of food-product allergens, thus protecting allergic patients from life-threatening events, including anaphylaxis, by unintentional consumption.

View details for DOI 10.1016/j.bios.2016.02.002

View details for PubMedID 26859787
Infant Infections and Respiratory Symptoms in Relation to in Utero Arsenic Exposure in a US Cohort ENVIRONMENTAL HEALTH PERSPECTIVES Farzan, S. F., Li, Z., Korrick, S. A., Spiegelman, D., Enelow, R., Nadeau, K., Baker, E., Karagas, M. R. 2016; 124 (6): 840-847
Abstract

Arsenic has been linked to disrupted immune function and greater infection susceptibility in highly exposed populations. Well arsenic levels above the U.S. EPA limit occur in our U.S. study area and are of particular concern for pregnant women and infants.We investigated whether in utero arsenic exposure affects the risk of infections and respiratory symptoms over the first year of life.We prospectively obtained information on infant infections and symptoms, including their duration and treatment (n = 412) at 4, 8, and 12 months using a parental telephone survey. Using generalized estimating equation models adjusted for potential confounders, we evaluated the association between maternal pregnancy urinary arsenic and infant infections and symptoms over the first year.Each doubling of maternal urinary arsenic was related to increases in the total number of infections requiring prescription medication in the first year [relative risk (RR) = 1.1; 95% CI: 1.0, 1.2]. Urinary arsenic was related specifically to respiratory symptoms (difficulty breathing, wheezing, and cough) lasting ? 2 days or requiring prescription medication (RR = 1.1; 95% CI: 1.0, 1.2; and RR = 1.2; 95% CI: 1.0, 1.5, respectively), and wheezing lasting ? 2 days, resulting in a doctor visit or prescription medication treatment (RR = 1.3; 95% CI: 1.0, 1.7; RR = 1.3; 95% CI: 1.0, 1.8, and RR = 1.5; 95% CI: 1.0, 2.2, respectively). Associations also were observed with diarrhea (RR = 1.4; 95% CI: 1.1, 1.9) and fever resulting in a doctor visit (RR = 1.2; 95% CI: 1.0, 1.5).In utero arsenic exposure was associated with a higher risk of infection during the first year of life in our study population, particularly infections requiring medical treatment, and with diarrhea and respiratory symptoms.Farzan SF, Li Z, Korrick SA, Spiegelman D, Enelow R, Nadeau K, Baker E, Karagas MR. 2016. Infant infections and respiratory symptoms in relation to in utero arsenic exposure in a U.S.Environ Health Perspect 124:840-847;?http://dx.doi.org/10.1289/ehp.1409282.

View details for DOI 10.1289/ehp.1409282

View details for Web of Science ID 000377081300028

View details for PubMedID 26359651

View details for PubMedCentralID PMC4892909
Identification and Characterization of a New Pecan [Carya illinoinensis (Wangenh.) K. Koch] Allergen, Car i 2 JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY Zhang, Y., Lee, B., Du, W., Lyu, S., Nadeau, K. C., Grauke, L. J., Zhang, Y., Wang, S., Fan, Y., Yi, J., McHugh, T. H. 2016; 64 (20): 4146-4151
Abstract

The 7S vicilin and 11S legumin seed storage globulins belong to the cupin protein superfamily and are major food allergens in many foods from the "big eight" food allergen groups. Here, for the first time, pecan vicilin was found to be a food allergen. Western blot experiments revealed that 30% of 27 sera used in this study and 24% of the sera from 25 patients with double-blind, placebo controlled clinical pecan allergy contained IgE antibodies specific to pecan vicilin. This allergen consists of a low-complexity region at its N-terminal and a structured domain at the C-terminal that contains two cupin motifs and forms homotrimers. The crystal structure of recombinant pecan vicilin was determined. The refined structure gave R/Rfree values of 0.218/0.262 for all data to 2.65 �. There were two trimeric biological units in the crystallographic asymmetric unit. Pecan vicilin is also a copper protein. These data may facilitate the understanding of the nutritional value and the allergenicity relevance of the copper binding property of seed storage proteins in tree nuts.

View details for DOI 10.1021/acs.jafc.6b00884

View details for PubMedID 27128197
Safety and feasibility of oral immunotherapy to multiple allergens for food allergy (vol 10, 1, 2014) ALLERGY ASTHMA AND CLINICAL IMMUNOLOGY Begin, P., Winterroth, L. C., Dominguez, T., Wilson, S. P., Bacal, L., Mehrotra, A., Kausch, B., Trela, A., Hoyte, E., O'Riordan, G., Seki, S., Blakemore, A., Woch, M., Hamilton, R. G., Nadeau, K. C. 2016; 12: 28
Abstract

[This corrects the article DOI: 10.1186/1710-1492-10-1.].

View details for PubMedID 27222658
Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange NATURE COMMUNICATIONS Pennington, L. F., Tarchevskaya, S., Brigger, D., Sathiyamoorthy, K., Graham, M. T., Nadeau, K. C., Eggel, A., Jardetzky, T. S. 2016; 7
Abstract

Omalizumab is a widely used therapeutic anti-IgE antibody. Here we report the crystal structure of the omalizumab-Fab in complex with an IgE-Fc fragment. This structure reveals the mechanism of omalizumab-mediated inhibition of IgE interactions with both high- and low-affinity IgE receptors, and explains why omalizumab selectively binds free IgE. The structure of the complex also provides mechanistic insight into a class of disruptive IgE inhibitors that accelerate the dissociation of the high-affinity IgE receptor from IgE. We use this structural data to generate a mutant IgE-Fc fragment that is resistant to omalizumab binding. Treatment with this omalizumab-resistant IgE-Fc fragment, in combination with omalizumab, promotes the exchange of cell-bound full-length IgE with omalizumab-resistant IgE-Fc fragments on human basophils. This combination treatment also blocks basophil activation more efficiently than either agent alone, providing a novel approach to probe regulatory mechanisms underlying IgE hypersensitivity with implications for therapeutic interventions.

View details for DOI 10.1038/ncomms11610

View details for Web of Science ID 000376111500001

View details for PubMedID 27194387

View details for PubMedCentralID PMC4873975
Molecular and cellular mechanisms of food allergy and food tolerance. journal of allergy and clinical immunology Chinthrajah, R. S., Hernandez, J. D., Boyd, S. D., Galli, S. J., Nadeau, K. C. 2016; 137 (4): 984-997
Abstract

Ingestion of innocuous antigens, including food proteins, normally results in local and systemic immune nonresponsiveness in a process termed oral tolerance. Oral tolerance to food proteins is likely to be intimately linked to mechanisms that are responsible for gastrointestinal tolerance to large numbers of commensal microbes. Here we review our current understanding of the immune mechanisms responsible for oral tolerance and how perturbations in these mechanisms might promote the loss of oral tolerance and development of food allergies. Roles for the commensal microbiome in promoting oral tolerance and the association of intestinal dysbiosis with food allergy are discussed. Growing evidence supports cutaneous sensitization to food antigens as one possible mechanism leading to the failure to develop or loss of oral tolerance. A�goal of immunotherapy for food allergies is to induce sustained desensitization or even true long-term oral tolerance to food allergens through mechanisms that might in part overlap with those associated with the development of natural oral tolerance.

View details for DOI 10.1016/j.jaci.2016.02.004

View details for PubMedID 27059726
A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Wood, R. A., Kim, J. S., Lindblad, R., Nadeau, K., Henning, A. K., Dawson, P., Plaut, M., Sampson, H. A. 2016; 137 (4): 1103-?
Abstract

Although studies of oral immunotherapy (OIT) for food allergy have shown promise, treatment is frequently complicated by adverse reactions and, even when successful, has limited long-term efficacy because benefits usually diminish when treatment is discontinued.We sought to examine whether the addition of omalizumab to milk OIT reduces treatment-related reactions, improves outcomes, or both.This was a double-blind, placebo-controlled trial with subjects randomized to omalizumab or placebo. Open-label milk OIT was initiated after 4 months of omalizumab/placebo with escalation to maintenance over 22 to 40 weeks, followed by daily maintenance dosing through month 28. At month 28, omalizumab was discontinued, and subjects passing an oral food challenge (OFC) continued OIT for 8 weeks, after which OIT was discontinued with rechallenge at month 32 to assess sustained unresponsiveness (SU).Fifty-seven subjects (7-32 years) were randomized, with no significant baseline differences in age, milk-specific IgE levels, skin test results, or OFC results. At month 28, 24 (88.9%) omalizumab-treated subjects and 20 (71.4%) placebo-treated subjects passed the 10-g "desensitization" OFC (P = .18). At month 32, SU was demonstrated in 48.1% in the omalizumab group and 35.7% in the placebo group (P = .42). Adverse reactions were markedly reduced during OIT escalation in omalizumab-treated subjects for percentages of doses per subject provoking symptoms (2.1% vs 16.1%, P = .0005), dose-related reactions requiring treatment (0.0% vs 3.8%, P = .0008), and doses required to achieve maintenance (198 vs 225, P = .008).In this first randomized, double-blind, placebo-controlled trial of omalizumab in combination with food OIT, we found significant improvements in measurements of safety but not in outcomes of efficacy (desensitization and SU).

View details for DOI 10.1016/j.jaci.2015.10.005

View details for Web of Science ID 000373351200016

View details for PubMedID 26581915
New tree nut allergens Zhang, Y., Du, W., Lee, B., Fan, Y., Lyn, S., Nadeau, K., McHugh, T. AMER CHEMICAL SOC. 2016
View details for Web of Science ID 000431903800062
Personal exposure to airborne particulate matter due to residential dryer lint cleaning BUILDING AND ENVIRONMENT Cheng, K., Zheng, D., Tetteh, A. O., Park, H., Nadeau, K. C., Hildemann, L. M. 2016; 98: 145-149
View details for DOI 10.1016/j.buildenv.2016.01.008

View details for Web of Science ID 000370995200015
T-Cell Immunophenotyping of Second-Hand Smoke-related Asthma. Annals of the American Thoracic Society Bauer, R. N., Chinthrajah, R. S., Andorf, S., Hobson, B., Miller, R. L., Nadeau, K. C. 2016; 13: S95-?
View details for DOI 10.1513/AnnalsATS.201507-457MG

View details for PubMedID 27027962
Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets. Proceedings of the National Academy of Sciences of the United States of America Ryan, J. F., Hovde, R., Glanville, J., Lyu, S., Ji, X., Gupta, S., Tibshirani, R. J., Jay, D. C., Boyd, S. D., Chinthrajah, R. S., Davis, M. M., Galli, S. J., Maecker, H. T., Nadeau, K. C. 2016; 113 (9): E1286-95
Abstract

Allergen immunotherapy can desensitize even subjects with potentially lethal allergies, but the changes induced in T cells that underpin successful immunotherapy remain poorly understood. In a cohort of peanut-allergic participants, we used allergen-specific T-cell sorting and single-cell gene expression to trace the transcriptional "roadmap" of individual CD4+ T cells throughout immunotherapy. We found that successful immunotherapy induces allergen-specific CD4+ T cells to expand and shift toward an "anergic" Th2 T-cell phenotype largely absent in both pretreatment participants and healthy controls. These findings show that sustained success, even after immunotherapy is withdrawn, is associated with the induction, expansion, and maintenance of immunotherapy-specific memory and naive T-cell phenotypes as early as 3 mo into immunotherapy. These results suggest an approach for immune monitoring participants undergoing immunotherapy to predict the success of future treatment and could have implications for immunotherapy targets in other diseases like cancer, autoimmune disease, and transplantation.

View details for DOI 10.1073/pnas.1520180113

View details for PubMedID 26811452
Trends in Adverse Reactions Requiring Epinephrine in the Build-up Phase of Oral Immunotherapy Noshirvan, A., Petroni, D. H., Tsai, M., Galli, S. J., Chinthrajah, R., Nadeau, K. C. MOSBY-ELSEVIER. 2016: AB131
View details for DOI 10.1016/j.jaci.2015.12.563

View details for Web of Science ID 000375005402124
Enhanced Efficacy and Confirmed Safety of a Two-Year Epicutaneous Immunotherapy (EPIT) Treatment of Peanut Allergy with Viaskin (R) Peanut: The Continuation of the Vipes Phase IIb Randomized Controlled Trial (RCT) Sampson, H. A., Agbotounou, W., Thebault, C., Ruban, C., Martin, L., Sussman, G. L., Brown-Whitehorn, T. F., Yang, W. H., Nadeau, K. C., Cheema, A., Leonard, S. A., Sauvage, C., Assa'ad, A. H., de Blay, F., Bird, J., Tilles, S. A., Boralevi, F., Bourrier, T., Benhamou, P., Dupont, C. MOSBY-ELSEVIER. 2016: AB408
View details for DOI 10.1016/j.jaci.2015.12.1264

View details for Web of Science ID 000375005405040
Fraction of Exhaled Nitric Oxide (FeNO) and Abdominal Pain and/or Vomiting in Reaction to Oral Food Challenge Slatkin, S. C., Tupa, D., Nadeau, K. C., Chinthrajah, R. MOSBY-ELSEVIER. 2016: AB135
View details for DOI 10.1016/j.jaci.2015.12.577

View details for Web of Science ID 000375005402138
Severity of Reactions to Oral Peanut Challenges in Children and Adults Chinthrajah, R., Rosa, J. S., Tupa, D., Smith, B., Gupta, R. S., Galli, S. J., Nadeau, K. C. MOSBY-ELSEVIER. 2016: AB134
View details for DOI 10.1016/j.jaci.2015.12.573

View details for Web of Science ID 000375005402134
Omalizumab Facilitates Rapid Oral Desensitization for Peanut Allergy Macginnitie, A. J., Rachid, R. A., Cianferoni, A., Dominguez, T. R., Heimall, J., Makhija, M. M., Robinson, R., Little, S. V., Gragg, H., Lakin, P., Logvinenko, T., LeBovidge, J. S., Koss, J., Ott, M. T., Rooney, C. B., Umetsu, D. T., Pongracic, J. A., Spergel, J. M., Nadeau, K. C., Schneider, L. C. MOSBY-ELSEVIER. 2016: AB194
View details for DOI 10.1016/j.jaci.2015.12.766

View details for Web of Science ID 000375005403079
Identification of Tr1 Cells and Other CD4+T Cell Subsets in Humans Using Mass Cytometry: A Tool for Understanding Asthma Prunicki, M., Zhou, X., Saguer, M., Miller, R., Nadeau, K. C. MOSBY-ELSEVIER. 2016: AB410
View details for DOI 10.1016/j.jaci.2015.12.1272

View details for Web of Science ID 000375005405048
Different Triggers for the Diagnosis of Individual Food Allergies in Multiple Food Allergic Patients Elizur, A., Bollyky, J. B., Block, W., Nadeau, K. C. MOSBY-ELSEVIER. 2016: AB156
View details for DOI 10.1016/j.jaci.2015.12.639

View details for Web of Science ID 000375005402200
In Vitro Induction of Peanut-Specific Tr1 Cells Pellerin, L., Jenks, J., Chinthrajah, R., Noshirvan, A., Nadeau, K. C., Roncarolo, M., Bacchetta, R. MOSBY-ELSEVIER. 2016: AB407
View details for DOI 10.1016/j.jaci.2015.12.1261

View details for Web of Science ID 000375005405037
Prediction and Identification of Korean Pine (Pinus koraiensis) Vicilin As a Food Zhang, Y., Du, W., Fan, Y., Nadeau, K. C., McHugh, T. H. MOSBY-ELSEVIER. 2016: AB267
View details for DOI 10.1016/j.jaci.2015.12.1011

View details for Web of Science ID 000375005404069
START: Susceptibility to Food Allergies in a Registry of Twins De Schryver, S., Dery, A., Clarke, A., Nadeau, K. C., Harada, L., Greenwood, C., Weatherall, K., Daley, D., Asai, Y., Bamforth, F., Ben-Shoshan, M. MOSBY-ELSEVIER. 2016: AB152
View details for DOI 10.1016/j.jaci.2015.12.627

View details for Web of Science ID 000375005402188
Exploring Correlations Between Cross-Reactive Tree Nuts in Multiple Food Allergic Patients Chang, A., Block, W., Bollyky, J. B., Chinthrajah, R., Nadeau, K. C., Elizur, A. MOSBY-ELSEVIER. 2016: AB200
View details for DOI 10.1016/j.jaci.2015.12.784

View details for Web of Science ID 000375005403097
Long-Term Follow-up of Oral Immunotherapy for Multiple Food Allergies Singh, S., Kshirsagar, R. A., Dominguez, T. R., Tupa, D., Block, W., Chinthrajah, R., Nadeau, K. C. MOSBY-ELSEVIER. 2016: AB132
View details for DOI 10.1016/j.jaci.2015.12.564

View details for Web of Science ID 000375005402125
Single B-cell deconvolution of peanut-specific antibody responses in allergic patients JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Hoh, R. A., Joshi, S. A., Liu, Y., Wang, C., Roskin, K. M., Lee, J., Pham, T., Looney, T. J., Jackson, K. J., Dixit, V. P., King, J., Lyu, S., Jenks, J., Hamilton, R. G., Nadeau, K. C., Boyd, S. D. 2016; 137 (1): 157-167
Abstract

The frequencies, cellular phenotypes, epitope specificity, and clonal diversity of allergen-specific B cells in patients with food allergy are not fully understood but are of major pathogenic and therapeutic significance.We sought to characterize peanut allergen-specific B-cell populations and the sequences and binding activities of their antibodies before and during immunotherapy.B cells binding fluorescently labeled Ara h 1 or Ara h 2 were phenotyped and isolated by means of flow cytometric sorting from 18 patients at baseline and 13 patients during therapy. Fifty-seven mAbs derived from allergen-binding single B cells were evaluated by using ELISA, Western blotting, and peptide epitope mapping. Deep sequencing of the B-cell repertoires identified additional members of the allergen-specific B-cell clones.Median allergen-binding B-cell frequencies were 0.0097% (Ara h 1) or 0.029% (Ara h 2) of B cells in baseline blood from allergic patients and approximately 3-fold higher during immunotherapy. Five of 57 allergen-specific cells belonged to clones containing IgE-expressing members. Almost all allergen-specific antibodies were mutated, and binding to both conformational and linear allergen epitopes was detected. Increasing somatic mutation of IgG4 members of a clone was seen in immunotherapy, whereas IgE mutation levels in the clone did not increase.Most peanut allergen-binding B cells isolated by means of antigen-specific flow sorting express mutated and isotype-switched antibodies. Immunotherapy increases their frequency in the blood, and even narrowly defined allergen epitopes are recognized by numerous distinct B-cell clones in a patient. The results also suggest that oral immunotherapy can stimulate somatic mutation of allergen-specific IgG4.

View details for DOI 10.1016/j.jaci.2015.05.029

View details for Web of Science ID 000367724300006
The Air We Breathe: How Extreme Weather Conditions Harm Us EXTREME WEATHER, HEALTH, AND COMMUNITIES: INTERDISCIPLINARY ENGAGEMENT STRATEGIES Prunicki, M. M., Nadeau, K. C., Steinberg, S. L., Sprigg, W. A. 2016: 293?310
View details for DOI 10.1007/978-3-319-30626-1_13

View details for Web of Science ID 000478777400014
Pilot randomised trial of a healthy eating behavioural intervention in uncontrolled asthma. The European respiratory journal Ma, J., Strub, P., Lv, N., Xiao, L., Camargo, C. A., Buist, A. S., Lavori, P. W., Wilson, S. R., Nadeau, K. C., Rosas, L. G. 2016; 47 (1): 122?32
Abstract

Rigorous research on the benefit of healthy eating patterns for asthma control is lacking.We randomised 90 adults with objectively confirmed uncontrolled asthma and a low-quality diet (Dietary Approaches to Stop Hypertension (DASH) scores <6 out of 9) to a 6-month DASH behavioural intervention (n=46) or usual-care control (n=44). Intention-to-treat analyses used repeated-measures mixed models.Participants were middle-aged, 67% female and multiethnic. Compared with controls, intervention participants improved on DASH scores (mean change (95% CI) 0.6 (0, 1.1) versus -0.3 (-0.8, 0.2); difference 0.8 (0.2, 1.5)) and the primary outcome, Asthma Control Questionnaire scores (-0.2 (-0.5, 0) versus 0 (-0.3, 0.3); difference -0.2 (-0.5, 0.1)) at 6 months. The mean group differences in changes in Mini Asthma Quality of Life Questionnaire overall and subdomain scores consistently favoured the intervention over the control group: overall 0.4 (95% CI 0, 0.8), symptoms 0.5 (0, 0.9), environment 0.4 (-0.1, 1.0), emotions 0.4 (-0.2, 0.9) and activities 0.3 (0, 0.7). These differences were modest, but potentially clinical significant.The DASH behavioural intervention improved diet quality with promising clinical benefits for better asthma control and functional status among adults with uncontrolled asthma. A full-scale efficacy trial is warranted.

View details for PubMedID 26493792
Allergen immunotherapy for IgE-mediated food allergy: protocol for a systematic review. Clinical and translational allergy Dhami, S., Nurmatov, U., Pajno, G. B., Fernandez-Rivas, M., Muraro, A., Roberts, G., Akdis, C., Alvaro-Lozano, M., Beyer, K., Bindslev-Jensen, C., Burks, W., Du Toit, G., Ebisawa, M., Eigenmann, P., Knol, E., Makela, M., Nadeau, K. C., O'mahony, L., Papadopoulos, N., Poulsen, L., Sackesen, C., Sampson, H., Santos, A., van Ree, R., Timmermans, F., Sheikh, A. 2016; 6: 24-?
Abstract

The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated food allergy. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT in IgE-mediated food allergy.We will undertake a systematic review, which will involve searching international biomedical databases for published, in progress and unpublished evidence. Studies will be independently screened against pre-defined eligibility criteria and critically appraised using established instruments. Data will be descriptively and, if possible and appropriate, quantitatively synthesised.The findings from this review will be used to inform the development of recommendations for EAACI's Guidelines on AIT.

View details for DOI 10.1186/s13601-016-0113-z

View details for PubMedID 27382460

View details for PubMedCentralID PMC4932703
Pilot randomised trial of a healthy eating behavioural intervention in uncontrolled asthma EUROPEAN RESPIRATORY JOURNAL Ma, J., Strub, P., Lv, N., Xiao, L., Camargo, C. A., Buist, A. S., Lavori, P. W., Wilson, S. R., Nadeau, K. C., Rosas, L. G. 2016; 47 (1): 122-132
Abstract

Rigorous research on the benefit of healthy eating patterns for asthma control is lacking.We randomised 90 adults with objectively confirmed uncontrolled asthma and a low-quality diet (Dietary Approaches to Stop Hypertension (DASH) scores <6 out of 9) to a 6-month DASH behavioural intervention (n=46) or usual-care control (n=44). Intention-to-treat analyses used repeated-measures mixed models.Participants were middle-aged, 67% female and multiethnic. Compared with controls, intervention participants improved on DASH scores (mean change (95% CI) 0.6 (0, 1.1) versus -0.3 (-0.8, 0.2); difference 0.8 (0.2, 1.5)) and the primary outcome, Asthma Control Questionnaire scores (-0.2 (-0.5, 0) versus 0 (-0.3, 0.3); difference -0.2 (-0.5, 0.1)) at 6 months. The mean group differences in changes in Mini Asthma Quality of Life Questionnaire overall and subdomain scores consistently favoured the intervention over the control group: overall 0.4 (95% CI 0, 0.8), symptoms 0.5 (0, 0.9), environment 0.4 (-0.1, 1.0), emotions 0.4 (-0.2, 0.9) and activities 0.3 (0, 0.7). These differences were modest, but potentially clinical significant.The DASH behavioural intervention improved diet quality with promising clinical benefits for better asthma control and functional status among adults with uncontrolled asthma. A full-scale efficacy trial is warranted.

View details for DOI 10.1183/13993003.00591-2015

View details for Web of Science ID 000367443900018

View details for PubMedCentralID PMC5136475
Mixing and sink effects of air purifiers on indoor PM2.5 concentrations: A pilot study of eight residential homes in Fresno, California AEROSOL SCIENCE AND TECHNOLOGY Cheng, K., Park, H., Tetteh, A. O., Zheng, D., Ouellette, N. T., Nadeau, K. C., Hildemann, L. M. 2016; 50 (8): 835-845
View details for DOI 10.1080/02786826.2016.1197375

View details for Web of Science ID 000379625400008
Gut Microbiome and the Development of Food Allergy and Allergic Disease PEDIATRIC CLINICS OF NORTH AMERICA Prince, B. T., Mandel, M. J., Nadeau, K., Singh, A. M. 2015; 62 (6): 1479-?
Abstract

The impact of gut microbiome on human development, nutritional needs, and disease has become evident with advances in the ability to study these complex communities of microorganisms, and there is growing appreciation for the role of the microbiome in immune regulation. Several studies have examined associations between changes in the commensal microbiota and the development of asthma, allergic rhinitis, and asthma, but far less have evaluated the impact of the microbiome on the development of food allergy. This article reviews the human gastrointestinal microbiome, focusing on the theory and evidence for its role in the development of IgE-mediated food allergy and other allergic diseases.

View details for DOI 10.1016/j.pcl.2015.07.007

View details for Web of Science ID 000364106500011

View details for PubMedID 26456445

View details for PubMedCentralID PMC4721650
Future Research Directions in Asthma An NHLBI Working Group Report AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Levy, B. D., Noel, P. J., Freemer, M. M., Cloutier, M. M., Georas, S. N., Jarjour, N. N., Ober, C., Woodruff, P., Barnes, K. C., Bender, B. G., Camargo, C. A., Chupp, G. L., Denlinger, L. C., Fahy, J. V., Fitzpatrick, A. M., Fuhlbrigge, A., Gaston, B. M., Hartert, T. V., Kolls, J. K., Lynch, S. V., Moore, W. C., Morgan, W. J., Nadeau, K. C., Ownby, D. R., Solway, J., Szefler, S. J., Wenzel, S. E., Wright, R. J., Smith, R. A., Erzurum, S. C. 2015; 192 (11): 1366-1372
Abstract

Asthma is a common chronic disease without cure. Our understanding of asthma onset, pathobiology, classification, and management has evolved substantially over the past decade; however, significant asthma-related morbidity and excess healthcare use and costs persist. To address this important clinical condition, the NHLBI convened a group of extramural investigators for an Asthma Research Strategic Planning workshop on September 18-19, 2014, to accelerate discoveries and their translation to patients. The workshop focused on (1) in utero and early-life origins of asthma, (2) the use of phenotypes and endotypes to classify disease, (3) defining disease modification, (4) disease management, and (5) implementation research. This report summarizes the workshop and produces recommendations to guide future research in asthma.

View details for DOI 10.1164/rccm.201505-0963WS

View details for Web of Science ID 000365829900017

View details for PubMedID 26305520

View details for PubMedCentralID PMC4731702
Diagnosis of Food Allergy PEDIATRIC CLINICS OF NORTH AMERICA Chinthrajah, R. S., Tupa, D., Prince, B. T., Block, W. M., Rosa, J. S., Singh, A. M., Nadeau, K. 2015; 62 (6): 1393-?
Abstract

The prevalence of food allergies has been on the increase over the last 2 decades. Diagnosing food allergies can be complicated, as there are multiple types that have distinct clinical and immunologic features. Food allergies are broadly classified into immunoglobulin E (IgE)-mediated, non-IgE-mediated, or mixed food allergic reactions. This review focuses on the clinical manifestations of the different categories of food allergies and the different tests available to guide the clinician toward an accurate diagnosis.

View details for DOI 10.1016/j.pcl.2015.07.009

View details for Web of Science ID 000364106500005

View details for PubMedID 26456439

View details for PubMedCentralID PMC5316471
Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency JOURNAL OF CLINICAL INVESTIGATION Walter, J. E., Rosen, L. B., Csomos, K., Rosenberg, J. M., Mathew, D., Keszei, M., Ujhazi, B., Chen, K., Lee, Y. N., Tirosh, I., Dobbs, K., Al-Herz, W., Cowan, M. J., Puck, J., Bleesing, J. J., Grimley, M. S., Malech, H., De Ravin, S. S., Gennery, A. R., Abraham, R. S., Joshi, A. Y., Boyce, T. G., Butte, M. J., Nadeau, K. C., Balboni, I., Sullivan, K. E., Akhter, J., Adeli, M., El-Feky, R. A., El-Ghoneimy, D. H., Dbaibo, G., Wakim, R., Azzari, C., Palma, P., Cancrini, C., Capuder, K., Condino-Neto, A., Costa-Carvalho, B. T., Oliveira, J. B., Roifman, C., Buchbinder, D., Kumanovics, A., Luis Franco, J., Niehues, T., Schuetz, C., Kuijpers, T., Yee, C., Chou, J., Masaad, M. J., Geha, R., Uze, G., Gelman, R., Holland, S. M., Recher, M., Utz, P. J., Browne, S. K., Notarangelo, L. D. 2015; 125 (11): 4135-4148
Abstract

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-? or anti-IFN-? antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

View details for DOI 10.1172/JCI80477

View details for Web of Science ID 000364110000017

View details for PubMedID 26457731
Human in vitro induced T regulatory cells and memory T cells share common demethylation of specific FOXP3 promoter region CLINICAL AND TRANSLATIONAL ALLERGY Begin, P., Schulze, J., Baron, U., Olek, S., Bauer, R. N., Passerini, L., Baccheta, R., Nadeau, K. C. 2015; 5
Abstract

The FOXP3 gene is the master regulator for T regulatory cells and is under tight DNA methylation control at the Treg specific demethylated region (TSDR) in its first intron. This said, methylation of its promoter region, the significance of which is unknown, has also been associated with various immune-related disease states such as asthma, food allergy, auto-immunity and cancer. Here, we used induced T regulatory cells (iTreg) as a target cell population to identify candidate hypomethylated CpG sites in the FOXP3 gene promoter to design a DNA methylation quantitative assay for this region.Three CpG sites at the promoter region showed clear demethylation pattern associated with high FOXP3 expression after activation in presence of TGF? and were selected as primary targets to design methylation-dependent RT-PCR primers and probes. We then examined the methylation of this 'inducible-promoter-demethylated-region' (IPDR) in various FOXP3+ T cell subsets. Both na�ve and memory thymic-derived Treg cells were found to be fully demethylated at both the IPDR and TSDR. Interestingly, in addition to iTregs, both CD25- and CD25(lo) conventional memory CD4+CD45RA- T cells displayed a high fraction of IPDR demethylated cells in absence of TSDR demethylation.This implies that the fraction of memory T cells should be taken in account when interpreting FOXP3 promoter methylation results from clinical studies. This approach, which is available for testing in clinical samples could have diagnostic and prognostic value in patients with immune or auto-inflammatory diseases.

View details for DOI 10.1186/s13601-015-0079-2

View details for Web of Science ID 000390101100001

View details for PubMedCentralID PMC4617722
IgH sequences in common variable immune deficiency reveal altered B cell development and selection. Science translational medicine Roskin, K. M., Simchoni, N., Liu, Y., Lee, J., Seo, K., Hoh, R. A., Pham, T., Park, J. H., Furman, D., Dekker, C. L., Davis, M. M., James, J. A., Nadeau, K. C., Cunningham-Rundles, C., Boyd, S. D. 2015; 7 (302): 302ra135-?
Abstract

Common variable immune deficiency (CVID) is the most common symptomatic primary immune deficiency, affecting ~1 in 25,000 persons. These patients suffer from impaired antibody responses, autoimmunity, and susceptibility to lymphoid cancers. To explore the cellular basis for these clinical phenotypes, we conducted high-throughput DNA sequencing of immunoglobulin heavy chain gene rearrangements from 93 CVID patients and 105 control subjects and sorted na�ve and memory B cells from 13 of the CVID patients and 10 of the control subjects. The CVID patients showed abnormal VDJ rearrangement and abnormal formation of complementarity-determining region 3 (CDR3). We observed a decreased selection against antibodies with long CDR3s in memory repertoires and decreased variable gene replacement, offering possible mechanisms for increased patient autoreactivity. Our data indicate that patient immunodeficiency might derive from both decreased diversity of the na�ve B cell pool and decreased somatic hypermutation in memory repertoires. The CVID patients also exhibited an abnormal clonal expansion of unmutated B cells relative to the controls. Although impaired B cell germinal center activation is commonly viewed as causative in CVID, these data indicate that CVID B cells diverge from controls as early as the pro-B stage, cell and suggest possible explanations for the increased incidence of autoimmunity, immunodeficiency, and lymphoma CVID patients.

View details for DOI 10.1126/scitranslmed.aab1216

View details for PubMedID 26311730
IgH sequences in common variable immune deficiency reveal altered B cell development and selection. Science translational medicine Roskin, K. M., Simchoni, N., Liu, Y., Lee, J., Seo, K., Hoh, R. A., Pham, T., Park, J. H., Furman, D., Dekker, C. L., Davis, M. M., James, J. A., Nadeau, K. C., Cunningham-Rundles, C., Boyd, S. D. 2015; 7 (302): 302ra135-?
Abstract

Common variable immune deficiency (CVID) is the most common symptomatic primary immune deficiency, affecting ~1 in 25,000 persons. These patients suffer from impaired antibody responses, autoimmunity, and susceptibility to lymphoid cancers. To explore the cellular basis for these clinical phenotypes, we conducted high-throughput DNA sequencing of immunoglobulin heavy chain gene rearrangements from 93 CVID patients and 105 control subjects and sorted na�ve and memory B cells from 13 of the CVID patients and 10 of the control subjects. The CVID patients showed abnormal VDJ rearrangement and abnormal formation of complementarity-determining region 3 (CDR3). We observed a decreased selection against antibodies with long CDR3s in memory repertoires and decreased variable gene replacement, offering possible mechanisms for increased patient autoreactivity. Our data indicate that patient immunodeficiency might derive from both decreased diversity of the na�ve B cell pool and decreased somatic hypermutation in memory repertoires. The CVID patients also exhibited an abnormal clonal expansion of unmutated B cells relative to the controls. Although impaired B cell germinal center activation is commonly viewed as causative in CVID, these data indicate that CVID B cells diverge from controls as early as the pro-B stage, cell and suggest possible explanations for the increased incidence of autoimmunity, immunodeficiency, and lymphoma CVID patients.

View details for DOI 10.1126/scitranslmed.aab1216

View details for PubMedID 26311730

View details for PubMedCentralID PMC4584259
The role of epigenetic mediation and the future of food allergy research SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY Quake, C., Nadeau, K. C. 2015; 43: 125-130
Abstract

IgE-mediated food allergy is a developing global health problem with prevalence rising at alarmingly fast rates. In this review, we discuss the interplay between genetics, epigenetics, and environmental exposures in the pathogenesis of food allergies. We aim to highlight the most recent evidence that suggests how epigenetic control may mediate genetic susceptibility of food allergies. We also examine how epigenetic modifications may be the key in explaining how environmental factors modulate and modify gene expression, leading to the dysregulation of immune tolerance and consequently, the development of food allergies. The emerging epigenetic paradigm in food allergies is likely to provide new mechanistic insight into food allergy risk and development as well as shape our therapeutic and preventive strategies.

View details for DOI 10.1016/j.semcdb.2015.07.002

View details for Web of Science ID 000364887100015

View details for PubMedID 26150170
PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. journal of allergy and clinical immunology Mathieu, A., Verronese, E., Rice, G. I., Fouyssac, F., Bertrand, Y., Picard, C., Chansel, M., Walter, J. E., Notarangelo, L. D., Butte, M. J., Nadeau, K. C., Csomos, K., Chen, D. J., Chen, K., Delgado, A., Rigal, C., Bardin, C., Schuetz, C., Moshous, D., Reumaux, H., Plenat, F., Phan, A., Zabot, M., Balme, B., Viel, S., Bienvenu, J., Cochat, P., van der Burg, M., Caux, C., Kemp, E. H., Rouvet, I., Malcus, C., M�ritet, J., Lim, A., Crow, Y. J., Fabien, N., M�n�trier-Caux, C., de Villartay, J., Walzer, T., Belot, A. 2015; 135 (6): 1578-88 e5
Abstract

PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance.We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients.Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency.We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T�cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in�vitro. The latter defect correlated in�vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1�had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells.Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.

View details for DOI 10.1016/j.jaci.2015.01.040

View details for PubMedID 25842288
Changes in peanut-specific T-cell clonotype with oral immunotherapy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Begin, P., Nadeau, K. C. 2015; 135 (6): 1636?38
View details for DOI 10.1016/j.jaci.2015.03.010

View details for Web of Science ID 000355933400027

View details for PubMedID 25930192
Review of Environmental Impact on the Epigenetic Regulation of Atopic Diseases CURRENT ALLERGY AND ASTHMA REPORTS Sabounchi, S., Bollyky, J., Nadeau, K. 2015; 15 (6)
Abstract

There has been significant increase in the prevalence of atopy over the past decade that cannot be explained by genetic predisposition. Environmental factors including nutrition, the uterine environment, and lifestyle factors are known to play a role in gene expression through epigenetic modifications. In this article, we review the literature on the environmental impact on epigenetic modulation of atopic diseases including asthma, food allergy, eczema, and allergic rhinitis. Recent public release of epigenomic data for hundreds of human tissues provides a powerful resource for further investigation of the molecular basis of atopic diseases.

View details for DOI 10.1007/s11882-015-0533-1

View details for Web of Science ID 000357428700004

View details for PubMedID 26141578
PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Mathieu, A., Verronese, E., Rice, G. I., Fouyssac, F., Bertrand, Y., Picard, C., Chansel, M., Walter, J. E., Notarangelo, L. D., Butte, M. J., Nadeau, K. C., Csomos, K., Chen, D. J., Chen, K., Delgado, A., Riga, C., Bardin, C., Schuetz, C., Moshous, D., Reumaux, H., Plenat, F., Phan, A., Zabot, M., Balme, B., Viel, S., Bienvenu, J., Cochat, P., van der Burg, M., Caux, C., Kemp, E. H., Rouvet, I., Malcus, C., Meritet, J., Lim, A., Crow, Y. J., Fabien, N., Menetrier-Caux, C., de Villartay, J., Walzer, T., Belot, A. 2015; 135 (6): 1578-U294
Abstract

PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance.We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients.Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency.We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T�cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in�vitro. The latter defect correlated in�vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1�had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells.Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.

View details for DOI 10.1016/j.jaci.2015.01.040

View details for Web of Science ID 000355933400021

View details for PubMedID 25842288

View details for PubMedCentralID PMC4487867
Review of Environmental Impact on the Epigenetic Regulation of Atopic Diseases. Current allergy and asthma reports Sabounchi, S., Bollyky, J., Nadeau, K. 2015; 15 (6): 33-?
Abstract

There has been significant increase in the prevalence of atopy over the past decade that cannot be explained by genetic predisposition. Environmental factors including nutrition, the uterine environment, and lifestyle factors are known to play a role in gene expression through epigenetic modifications. In this article, we review the literature on the environmental impact on epigenetic modulation of atopic diseases including asthma, food allergy, eczema, and allergic rhinitis. Recent public release of epigenomic data for hundreds of human tissues provides a powerful resource for further investigation of the molecular basis of atopic diseases.

View details for DOI 10.1007/s11882-015-0533-1

View details for PubMedID 26141578
Ambient polycyclic aromatic hydrocarbons and pulmonary function in children JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY Padula, A. M., Balmes, J. R., Eisen, E. A., Mann, J., Noth, E. M., Lurmann, F. W., Pratt, B., Tager, I. B., Nadeau, K., Hammond, S. K. 2015; 25 (3): 295-302
Abstract

Few studies have examined the relationship between ambient polycyclic aromatic hydrocarbons (PAHs) and pulmonary function in children. Major sources include vehicular emissions, home heating, wildland fires, agricultural burning, and power plants. PAHs are an important component of fine particulate matter that has been linked to respiratory health. This cross-sectional study examines the relationship between estimated individual exposures to the sum of PAHs with 4, 5, or 6 rings (PAH456) and pulmonary function tests (forced expiratory volume in one second (FEV1) and forced expiratory flow between 25% and 75% of vital capacity) in asthmatic and non-asthmatic children. We applied land-use regression to estimate individual exposures to ambient PAHs for averaging periods ranging from 1 week to 1 year. We used linear regression to estimate the relationship between exposure to PAH456 with pre- and postbronchodilator pulmonary function tests in children in Fresno, California (N=297). Among non-asthmatics, there was a statistically significant association between PAH456 during the previous 3 months, 6 months, and 1 year and postbronchodilator FEV1. The magnitude of the association increased with the length of the averaging period ranging from 60 to 110?ml decrease in FEV1 for each 1?ng/m(3) increase in PAH456. There were no associations with PAH456 observed among asthmatic children. We identified an association between annual PAHs and chronic pulmonary function in children without asthma. Additional studies are needed to further explore the association between exposure to PAHs and pulmonary function, especially with regard to differential effects between asthmatic and non-asthmatic children.Journal of Exposure Science and Environmental Epidemiology advance online publication, 18 June 2014; doi:10.1038/jes.2014.42.

View details for DOI 10.1038/jes.2014.42

View details for Web of Science ID 000353405500009

View details for PubMedID 24938508
Deep profiling of single T cell receptor repertoire and phenotype with targeted RNA-seq Ji, X., Lyu, S., Spindler, M., Bacchetta, R., Goncharov, I., Han, A., Glanville, J., Wang, W., Roncarolo, M., Meyer, E., Nadeau, K., Maecker, H. AMER ASSOC IMMUNOLOGISTS. 2015
View details for Web of Science ID 000379404504197
Basophil surface expressions of CD203c and CD63 following peanut allergen ex vivo stimulation correlate with severity of allergic reactions during food challenge Rosa, J., Chinthrajah, R., Dominguez, T., Brock, E., Nadeau, K. AMER ASSOC IMMUNOLOGISTS. 2015
View details for Web of Science ID 000379404502262
The future of biologics: Applications for food allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Bauer, R. N., Manohar, M., Singh, A. M., Jay, D. C., Nadeau, K. C. 2015; 135 (2): 312-323
Abstract

Allergic diseases affect millions worldwide, with growing evidence of an increase in allergy occurrence over the past few decades. Current treatments for allergy include corticosteroids to reduce inflammation and allergen immunotherapy; however, some subjects experience treatment-resistant inflammation or adverse reactions to these treatments, and there are currently no approved therapeutics for the treatment of food allergy. There is a dire need for new therapeutic approaches for patients with poorly controlled atopic diseases and a need to improve the safety and effectiveness of allergen immunotherapy. Improved understanding of allergy through animal models and clinical trials has unveiled potential targets for new therapies, leading to the development of several biologics to treat allergic diseases. This review focuses on the mechanisms that contribute to allergy, with an emphasis on future targets for biologics for the treatment of food allergy. These biologics include immunotherapy with novel anti-IgE antibodies and analogs, small-molecule inhibitors of cell signaling, anti-type 2 cytokine mAbs, and TH1-promoting adjuvants.

View details for DOI 10.1016/j.jaci.2014.12.1908

View details for Web of Science ID 000349372300002
Epicutaneous Immunotherapy (EPIT) Is Effective and Safe to Treat Peanut Allergy: A Multi-National Double-Blind PlaceboControlled Randomized Phase IIb Trial Sampson, H. A., Agbotounou, W., Thebault, C., Charles, R., Martin, L., Yang, W. H., Sussman, G. L., Brown-Whitehorn, T. F., Nadeau, K. C., Cheema, A., Leonard, S. A., Pongracic, J. A., Sauvage, C., Assa'ad, A. H., de Blay, F., Bird, J., Tilles, S. A., Boralevi, F., Bourrier, T., Shreffler, W. G., Hebert, J., Green, T., van Wijk, R., Knulst, A. C., Kanny, G., Kowalski, M. L., Schneider, L. C., Benhamou, P., Dupont, C. MOSBY-ELSEVIER. 2015: AB390
View details for DOI 10.1016/j.jaci.2014.12.1901

View details for Web of Science ID 000361129600947
Intravenous anti-IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis. journal of allergy and clinical immunology Rothenberg, M. E., Wen, T., Greenberg, A., Alpan, O., Enav, B., Hirano, I., Nadeau, K., Kaiser, S., Peters, T., Perez, A., Jones, I., Arm, J. P., Strieter, R. M., Sabo, R., Gunawardena, K. A. 2015; 135 (2): 500-507
Abstract

Eosinophilic esophagitis (EoE) is a chronic allergic disease with limited treatment options.We evaluated QAX576, an mAb against IL-13, in the treatment of patients with EoE.Patients (18-50 years) with proton pump inhibitor-resistant esophageal eosinophilia received intravenous QAX576 (6 mg/kg) or placebo (2:1) at weeks 0, 4, and 8 and were followed for 6 months. The primary end point was the responder rate for a greater than 75% decrease in peak eosinophil counts at week 12. Efficacy was to be declared if the lower 90% confidence limit for the proportion of responders on QAX576 was 35% or greater. Secondary end points included changes in esophageal eosinophil counts, symptoms assessed by questionnaire scores, and quantification of a series of biomarkers.Twenty-three patients completed the study up to week 12, and 18 continued to the end of the study. For the proximal and distal esophageal biopsies combined, the responder rate was 12.5% (90% confidence limit, 1% to 43%) with placebo, compared to 40.0% (90% confidence limit, 22% to 61%) with QAX576. Although the primary end point was not met, the mean esophageal eosinophil count decreased by 60% with QAX576 versus an increase of 23% with placebo (P = .004), and the decrease was sustained up to 6 months. There was a trend for improved symptoms, particularly dysphagia. QAX576 improved expression of EoE-relevant esophageal transcripts, including eotaxin-3, periostin, and markers of mast cells and barrier function, for up to 6 months after treatment. QAX576 was well tolerated.QAX576 significantly improved intraepithelial esophageal eosinophil counts and dysregulated esophageal disease-related transcripts in adults with EoE in a sustained manner.

View details for DOI 10.1016/j.jaci.2014.07.049

View details for PubMedID 25226850
Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children NATURE COMMUNICATIONS Hong, X., Hao, K., Ladd-Acosta, C., Hansen, K. D., Tsai, H., Liu, X., Xu, X., Thornton, T. A., Caruso, D., Keet, C. A., Sun, Y., Wang, G., Luo, W., Kumar, R., Fuleihan, R., Singh, A. M., Kim, J. S., Story, R. E., Gupta, R. S., Gao, P., Chen, Z., Walker, S. O., Bartell, T. R., Beaty, T. H., Fallin, M. D., Schleimer, R., Holt, P. G., Nadeau, K. C., Wood, R. A., Pongracic, J. A., Weeks, D. E., Wang, X. 2015; 6
Abstract

Food allergy (FA) affects 2%-10% of US children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk and egg) in 2,759 US participants (1,315 children and 1,444 parents) from the Chicago Food Allergy Study, and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (P=5.5 � 10(-8)) and rs9275596 (P=6.8 � 10(-10)), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (P<5 � 10(-8)), and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region probably poses significant genetic risk for PA.

View details for DOI 10.1038/ncomms7304

View details for Web of Science ID 000350290300002

View details for PubMedID 25710614

View details for PubMedCentralID PMC4340086
The future of biologics: applications for food allergy. journal of allergy and clinical immunology Bauer, R. N., Manohar, M., Singh, A. M., Jay, D. C., Nadeau, K. C. 2015; 135 (2): 312-323
Abstract

Allergic diseases affect millions worldwide, with growing evidence of an increase in allergy occurrence over the past few decades. Current treatments for allergy include corticosteroids to reduce inflammation and allergen immunotherapy; however, some subjects experience treatment-resistant inflammation or adverse reactions to these treatments, and there are currently no approved therapeutics for the treatment of food allergy. There is a dire need for new therapeutic approaches for patients with poorly controlled atopic diseases and a need to improve the safety and effectiveness of allergen immunotherapy. Improved understanding of allergy through animal models and clinical trials has unveiled potential targets for new therapies, leading to the development of several biologics to treat allergic diseases. This review focuses on the mechanisms that contribute to allergy, with an emphasis on future targets for biologics for the treatment of food allergy. These biologics include immunotherapy with novel anti-IgE antibodies and analogs, small-molecule inhibitors of cell signaling, anti-type 2 cytokine mAbs, and TH1-promoting adjuvants.

View details for DOI 10.1016/j.jaci.2014.12.1908

View details for PubMedID 25662303
Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells. Clinical and experimental allergy Hew, K. M., WALKER, A. I., Kohli, A., Garcia, M., Syed, A., McDonald-Hyman, C., Noth, E. M., Mann, J. K., Pratt, B., Balmes, J., Hammond, S. K., Eisen, E. A., Nadeau, K. C. 2015; 45 (1): 238-248
Abstract

Evidence suggests that exposure to polycyclic aromatic hydrocarbons (PAHs) increases atopy; it is unclear how PAH exposure is linked to increased severity of atopic diseases.We hypothesized that ambient PAH exposure is linked to impairment of immunity in atopic children (defined as children with asthma and/or allergic rhinitis) from Fresno, California, an area with elevated ambient PAHs.We recruited 256 subjects from Fresno, CA. Ambient PAH concentrations (ng/m(3) ) were measured using a spatial-temporal regression model over multiple time periods. Asthma diagnosis was determined by current NHLBI criteria. Phenotyping and functional immune measurements were performed from isolated cells. For epigenetic measurements, DNA was isolated and pyrosequenced.We show that higher average PAH exposure was significantly associated with impaired Treg function and increased methylation in the forkhead box protein 3 (FOXP3) locus (P�<�0.05), conditional on atopic status. These epigenetic modifications were significantly linked to differential protein expression of FOXP3 (P�<�0.001). Methylation was associated with cellular functional changes, specifically Treg dysfunction, and an increase in total plasma IgE levels. Protein expression of IL-10 decreased and IFN-? increased as the extent of PAH exposure increased. The strength of the associations generally increased as the time window for average PAH exposure increased from 24�hr to 1�year, suggesting more of a chronic response. Significant associations with chronic PAH exposure and immune outcomes were also observed in subjects with allergic rhinitis.Collectively, these results demonstrate that increased ambient PAH exposure is associated with impaired systemic immunity and epigenetic modifications in a key locus involved in atopy: FOXP3, with a higher impact on atopic children. The results suggest that increased atopic clinical symptoms in children could be linked to increased PAH exposure in air pollution.

View details for DOI 10.1111/cea.12377

View details for PubMedID 25048800
Single B-cell deconvolution of peanut-specific antibody responses in allergic patients. The Journal of allergy and clinical immunology Hoh, R. A., Joshi, S. A., Liu, Y., Wang, C., Roskin, K. M., Lee, J. Y., Pham, T., Looney, T. J., Jackson, K. J., Dixit, V. P., King, J., Lyu, S. C., Jenks, J., Hamilton, R. G., Nadeau, K. C., Boyd, S. D. 2015
Abstract

The frequencies, cellular phenotypes, epitope specificity, and clonal diversity of allergen-specific B cells in patients with food allergy are not fully understood but are of major pathogenic and therapeutic significance.We sought to characterize peanut allergen-specific B-cell populations and the sequences and binding activities of their antibodies before and during immunotherapy.B cells binding fluorescently labeled Ara h 1 or Ara h 2 were phenotyped and isolated by means of flow cytometric sorting from 18 patients at baseline and 13 patients during therapy. Fifty-seven mAbs derived from allergen-binding single B cells were evaluated by using ELISA, Western blotting, and peptide epitope mapping. Deep sequencing of the B-cell repertoires identified additional members of the allergen-specific B-cell clones.Median allergen-binding B-cell frequencies were 0.0097% (Ara h 1) or 0.029% (Ara h 2) of B cells in baseline blood from allergic patients and approximately 3-fold higher during immunotherapy. Five of 57 allergen-specific cells belonged to clones containing IgE-expressing members. Almost all allergen-specific antibodies were mutated, and binding to both conformational and linear allergen epitopes was detected. Increasing somatic mutation of IgG4 members of a clone was seen in immunotherapy, whereas IgE mutation levels in the clone did not increase.Most peanut allergen-binding B cells isolated by means of antigen-specific flow sorting express mutated and isotype-switched antibodies. Immunotherapy increases their frequency in the blood, and even narrowly defined allergen epitopes are recognized by numerous distinct B-cell clones in a patient. The results also suggest that oral immunotherapy can stimulate somatic mutation of allergen-specific IgG4.

View details for PubMedID 26152318
Human in vitro induced T regulatory cells and memory T cells share common demethylation of specific FOXP3 promoter region. Clinical and translational allergy B�gin, P., Schulze, J., Baron, U., Olek, S., Bauer, R. N., Passerini, L., Baccheta, R., Nadeau, K. C. 2015; 5: 35-?
Abstract

The FOXP3 gene is the master regulator for T regulatory cells and is under tight DNA methylation control at the Treg specific demethylated region (TSDR) in its first intron. This said, methylation of its promoter region, the significance of which is unknown, has also been associated with various immune-related disease states such as asthma, food allergy, auto-immunity and cancer. Here, we used induced T regulatory cells (iTreg) as a target cell population to identify candidate hypomethylated CpG sites in the FOXP3 gene promoter to design a DNA methylation quantitative assay for this region.Three CpG sites at the promoter region showed clear demethylation pattern associated with high FOXP3 expression after activation in presence of TGF? and were selected as primary targets to design methylation-dependent RT-PCR primers and probes. We then examined the methylation of this 'inducible-promoter-demethylated-region' (IPDR) in various FOXP3+ T cell subsets. Both na�ve and memory thymic-derived Treg cells were found to be fully demethylated at both the IPDR and TSDR. Interestingly, in addition to iTregs, both CD25- and CD25(lo) conventional memory CD4+CD45RA- T cells displayed a high fraction of IPDR demethylated cells in absence of TSDR demethylation.This implies that the fraction of memory T cells should be taken in account when interpreting FOXP3 promoter methylation results from clinical studies. This approach, which is available for testing in clinical samples could have diagnostic and prognostic value in patients with immune or auto-inflammatory diseases.

View details for DOI 10.1186/s13601-015-0079-2

View details for PubMedID 26500760

View details for PubMedCentralID PMC4617722
The evolution of allergen and non-specific immunotherapy: past achievements, current applications and future outlook EXPERT REVIEW OF CLINICAL IMMUNOLOGY Pajno, G. B., Nadeau, K. C., Passalacqua, G., Caminiti, L., Hobson, B., Jay, D. C., Arasi, S., Chiera, F., Salzano, G. 2015; 11 (1): 141-154
Abstract

Recent epidemiological studies estimated that more than 30% of European suffer from allergic rhinitis or conjunctivitis, while up to 20% suffer from asthma and 15% from allergic skin conditions, while for many other regions the prevalence is increasing. Allergen immunotherapy represents the only available treatment that can modify the allergic disease process, and thus is worth considering as a treatment in affected individuals. A beneficial effect of allergen immunotherapy has been shown in both adults and children affected by allergic rhinitis, allergic conjunctivitis, allergic asthma and hymenoptera venom allergy. The present study represents an overview on allergen immunotherapy, focusing on the principal aspects of the use of immunotherapy in the past, its recent clinical applications and future outlook.

View details for DOI 10.1586/1744666X.2015.977260

View details for Web of Science ID 000346760700011

View details for PubMedID 25454510
Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children. Nature communications Hong, X., Hao, K., Ladd-Acosta, C., Hansen, K. D., Tsai, H., Liu, X., Xu, X., Thornton, T. A., Caruso, D., Keet, C. A., Sun, Y., Wang, G., Luo, W., Kumar, R., Fuleihan, R., Singh, A. M., Kim, J. S., Story, R. E., Gupta, R. S., Gao, P., Chen, Z., Walker, S. O., Bartell, T. R., Beaty, T. H., Fallin, M. D., Schleimer, R., Holt, P. G., Nadeau, K. C., Wood, R. A., Pongracic, J. A., Weeks, D. E., Wang, X. 2015; 6: 6304-?
Abstract

Food allergy (FA) affects 2%-10% of US children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk and egg) in 2,759 US participants (1,315 children and 1,444 parents) from the Chicago Food Allergy Study, and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (P=5.5 � 10(-8)) and rs9275596 (P=6.8 � 10(-10)), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (P<5 � 10(-8)), and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region probably poses significant genetic risk for PA.

View details for DOI 10.1038/ncomms7304

View details for PubMedID 25710614
Exome sequencing and genome-wide copy number variant mapping reveal novel associations with sensorineural hereditary hearing loss BMC GENOMICS Haraksingh, R. R., Jahanbani, F., Rodriguez-Paris, J., Gelernter, J., Nadeau, K. C., Oghalai, J. S., Schrijver, I., Snyder, M. P. 2014; 15
Abstract

The genetic diversity of loci and mutations underlying hereditary hearing loss is an active area of investigation. To identify loci associated with predominantly non-syndromic sensorineural hearing loss, we performed exome sequencing of families and of single probands, as well as copy number variation (CNV) mapping in a case-control cohort.Analysis of three distinct families revealed several candidate loci in two families and a single strong candidate gene, MYH7B, for hearing loss in one family. MYH7B encodes a Type II myosin, consistent with a role for cytoskeletal proteins in hearing. High-resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known to be involved in hearing (e.g. GJB6, OTOA, and STRC, encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR = 3.91, 95% CI: 1.62-9.40, p = 1.45 x 10-7).We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the etiology of hearing loss. Our study also demonstrates the challenges of exome sequencing and genome-wide CNV mapping for direct clinical application, and illustrates the need for functional and clinical follow-up as well as curated open-access databases.

View details for DOI 10.1186/1471-2164-15-1155

View details for Web of Science ID 000209598100001
In utero arsenic exposure and fetal immune repertoire in a US pregnancy cohort CLINICAL IMMUNOLOGY Nadeau, K. C., Li, Z., Farzan, S., Koestler, D., Robbins, D., Fei, D. L., Malipatlolla, M., Maecker, H., Enelow, R., Korrick, S., Karagas, M. R. 2014; 155 (2): 188-197
Abstract

Arsenic has wide-ranging effects on human health and there is evidence that it alters the immune response by influencing CD4+/CD8+ T cell ratios, IL-2 cytokine levels, and the expression of immune-response genes. We investigated the impact of in utero environmental arsenic exposure on immune development and function in newborns participating in a pregnancy cohort in New Hampshire, U.S., where arsenic levels have exceeded the current EPA maximum contaminant level of 10 ?g/L. Our results showed that maternal urinary arsenic concentrations were inversely related to absolute total CD45RA+ CD4+ cord blood CD69+ T cell counts (N=116, p=0.04) and positively associated with CD45RA+ CD69- CD294+ cell counts (p=0.01). In placental samples (N=70), higher in utero urinary arsenic concentrations were positively associated with the expression of IL1? (p=0.03). These data provide evidence that relatively low-level arsenic exposure in utero may alter the fetal immune system and lead to immune dysregulation.

View details for DOI 10.1016/j.clim.2014.09.004

View details for Web of Science ID 000346114300004

View details for PubMedID 25229165

View details for PubMedCentralID PMC4309995
Two year effects of food allergen immunotherapy on quality of life in caregivers of children with food allergies ALLERGY ASTHMA AND CLINICAL IMMUNOLOGY Arasi, S., Otani, I. M., Klingbeil, E., Begin, P., Kearney, C., Dominguez, T. L., Block, W. M., O'Riordan, G., Nadeau, K. C. 2014; 10
Abstract

Food allergy (FA) can have serious psychosocial and economic repercussions on food-allergic children and their caregivers and be associated with negative effects on their quality of life. Food allergen immunotherapy (IT) is a promising experimental therapy but can be linked to anxiety. This study investigated the effects of IT on FA-specific health-related quality of life (HRQL) over a 24�month-follow-up in caregivers of children with single and multiple food allergies. We hypothesized that characteristics such as age, asthma at baseline and respiratory allergic reactions during therapy were key characteristics that influenced HRQL scores.A validated Food Allergy Quality of Life - Parental Burden Questionnaire (FAQL-PB) was used to assess HRQL. It was randomly distributed to and filled out by caregivers of 57 food-allergic children enrolled in clinical trials of IT. The same parent answered the FABQL-PB questionnaire at baseline and for 6-month, 12- month, 18- month, and 24-month time points on IT.Caregiver HRQL improved significantly (change?
View details for DOI 10.1186/1710-1492-10-57

View details for Web of Science ID 000346026400001

View details for PubMedCentralID PMC4363059
Lessons learned from mice and man: Mimicking human allergy through mouse models CLINICAL IMMUNOLOGY Graham, M. T., Nadeau, K. C. 2014; 155 (1): 1-16
Abstract

The relevance of using mouse models to represent human allergic pathologies is still unclear. Recent studies suggest the limitations of using models as a standard for assessing immune response and tolerance mechanisms, as mouse models often do not sufficiently depict human atopic conditions. Allergy is a combination of aberrant responses to innocuous environmental agents and the subsequent TH2-mediated inflammatory responses. In this review, we will discuss current paradigms of allergy - specifically, TH2-mediated and IgE-associated immune responses - and current mouse models used to recreate these TH2-mediated pathologies. Our overall goal is to highlight discrepancies that exist between mice and men by examining the advantages and disadvantages of allergic mouse models with respect to the human allergic condition.

View details for DOI 10.1016/j.clim.2014.08.002

View details for Web of Science ID 000343638400002
Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Alexander, E. S., Martin, L. J., Collins, M. H., Kottyan, L. C., Sucharew, H., He, H., Mukkada, V. A., Succop, P. A., Abonia, J. P., Foote, H., Eby, M. D., Grotjan, T. M., Greenler, A. J., Dellon, E. S., Demain, J. G., Furuta, G. T., Gurian, L. E., Harley, J. B., Hopp, R. J., Kagalwalla, A., Kaul, A., Nadeau, K. C., Noel, R. J., Putnam, P. E., von Tiehl, K. F., Rothenberg, M. E. 2014; 134 (5): 1084-?
Abstract

Eosinophilic esophagitis (EoE) is a chronic antigen-driven allergic inflammatory disease, likely involving the interplay of genetic and environmental factors, yet their respective contributions to heritability are unknown.To quantify the risk associated with genes and environment on familial clustering of EoE.Family history was obtained from a hospital-based cohort of 914 EoE probands (n = 2192 first-degree "Nuclear-Family" relatives) and an international registry of monozygotic and dizygotic twins/triplets (n = 63 EoE "Twins" probands). Frequencies, recurrence risk ratios (RRRs), heritability, and twin concordance were estimated. Environmental exposures were preliminarily examined.Analysis of the Nuclear-Family-based cohort revealed that the rate of EoE, in first-degree relatives of a proband, was 1.8% (unadjusted) and 2.3% (sex-adjusted). RRRs ranged from 10 to 64, depending on the family relationship, and were higher in brothers (64.0; P = .04), fathers (42.9; P = .004), and males (50.7; P < .001) than in sisters, mothers, and females, respectively. The risk of EoE for other siblings was 2.4%. In the Nuclear-Family cohort, combined gene and common environment heritability was 72.0% � 2.7% (P < .001). In the Twins cohort, genetic heritability was 14.5% � 4.0% (P < .001), and common family environment contributed 81.0% � 4% (P < .001) to phenotypic variance. Probandwise concordance in monozygotic co-twins was 57.9% � 9.5% compared with 36.4% � 9.3% in dizygotic co-twins (P = .11). Greater birth weight difference between twins (P = .01), breast-feeding (P = .15), and fall birth season (P = .02) were associated with twin discordance in disease status.EoE RRRs are increased 10- to 64-fold compared with the general population. EoE in relatives is 1.8% to 2.4%, depending on relationship and sex. Nuclear-Family heritability appeared to be high (72.0%). However, the Twins cohort analysis revealed a powerful role for common environment (81.0%) compared with additive genetic heritability (14.5%).

View details for DOI 10.1016/j.jaci.2014.07.021

View details for Web of Science ID 000344938900013

View details for PubMedCentralID PMC4253562
GWAS identifies four novel eosinophilic esophagitis loci NATURE COMMUNICATIONS Sleiman, P. M., Wang, M., Cianferoni, A., Aceves, S., Gonsalves, N., Nadeau, K., Bredenoord, A. J., Furuta, G. T., Spergel, J. M., Hakonarson, H. 2014; 5
Abstract

Eosinophilic esophagitis (EoE) is an allergic disorder characterized by infiltration of the oesophagus with eosinophils. We had previously reported association of the TSLP/WDR36 locus with EoE. Here we report genome-wide significant associations at four additional loci; c11orf30 and STAT6, which have been previously associated with both atopic and autoimmune diseases, and two EoE-specific loci, ANKRD27 that regulates the trafficking of melanogenic enzymes to epidermal melanocytes and CAPN14, that encodes a calpain whose expression is highly enriched in the oesophagus. The identification of five EoE loci, not only expands our aetiological understanding of the disease but may also represent new therapeutic targets to treat the most debilitating aspect of EoE, oesophageal inflammation and remodelling.

View details for DOI 10.1038/ncomms6593

View details for Web of Science ID 000346082000003

View details for PubMedID 25407941

View details for PubMedCentralID PMC4238044
Food allergy: A practice parameter update-2014 JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Sampson, H. A., Aceves, S., Bock, S. A., James, J., Jones, S., Lang, D., Nadeau, K., Nowak-Wegrzyn, A., Oppenheimer, J., Perry, T. T., Randolph, C., Sicherer, S. H., Simon, R. A., Vickery, B. P., Wood, R. 2014; 134 (5): 1016-?
Abstract

This parameter was developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology (JCAAI). The AAAAI and the ACAAI have jointly accepted responsibility for�establishing "Food Allergy: A�practice parameter update-2014." This is a complete and comprehensive document at the current time. The medical environment is a changing one, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, ACAAI, and JCAAI. These parameters are not designed for use by pharmaceutical companies in drug promotion.

View details for DOI 10.1016/j.jaci.2014.05.013

View details for Web of Science ID 000344938900004

View details for PubMedID 25174862
Immune Mechanisms of Sublingual Immunotherapy CURRENT ALLERGY AND ASTHMA REPORTS Jay, D. C., Nadeau, K. C. 2014; 14 (11)
Abstract

Sublingual immunotherapy (SLIT) is a well-established allergen-specific immunotherapy and a safe and effective strategy to reorient inappropriate immune responses in allergic patients. SLIT takes advantage of the tolerogenic environment of the oral mucosa to promote tolerance to the allergen. Several clinical studies have investigated the complex interplay of innate and adaptive immune responses that SLIT exploits. The oral immune system is composed of tolerogenic dendritic cells that, following uptake of allergen during SLIT, support the differentiation of T helper cell type 1 (Th1) and the induction of IL-10-producing regulatory T cells. Following SLIT, allergic disease-promoting T helper cell type 2 (Th2) responses shift to a Th1 inflammatory response, and IL-10 and transforming growth factor (TGF)-? production by regulatory T cells and tolerogenic dendritic cells suppress allergen-specific T cell responses. These immune changes occur both in the sublingual mucosa and in the periphery of a patient following SLIT. SLIT also promotes the synthesis of allergen-specific IgG and IgA antibodies that block allergen-IgE complex formation and binding to inflammatory cells, thus encouraging an anti-inflammatory environment. Several of these revealing findings have also paved the way for the identification of biomarkers of the clinical efficacy of SLIT. This review presents the emerging elucidation of the immune mechanisms mediated by SLIT.

View details for DOI 10.1007/s11882-014-0473-1

View details for Web of Science ID 000343644500004

View details for PubMedID 25195100
Long-term Sinonasal Outcomes of Aspirin Desensitization in Aspirin Exacerbated Respiratory Disease OTOLARYNGOLOGY-HEAD AND NECK SURGERY Cho, K., Soudry, E., Psaltis, A. J., Nadeau, K. C., McGhee, S. A., Nayak, J. V., Hwang, P. H. 2014; 151 (4): 575-581
Abstract

This study aimed to assess sinonasal outcomes in patients with aspirin exacerbated respiratory disease (AERD) undergoing aspirin desensitization following endoscopic sinus surgery (ESS).Case series with chart review.University hospital.A retrospective review of sinonasal outcomes was conducted for 30 AERD patients undergoing aspirin desensitization and maintenance therapy following ESS. Sinonasal outcomes were prospectively assessed by the Sinonasal Outcomes Test-22 (SNOT-22) and endoscopic polyp grading system. Data were collected preoperatively, 1 and 4 weeks postsurgery (before desensitization), and 1, 6, 12, 18, 24, and 30 months after aspirin desensitization.Twenty-eight of 30 patients (93.3%) successfully completed aspirin desensitization, whereas 2 of 30 (6.7%) were unable to complete desensitization due to respiratory intolerance. Of the 21 patients who successfully completed a minimum of 24 weeks of follow-up, 20 (95.2%) patients demonstrated sustained endoscopic and symptomatic improvement for a median follow-up period of 33 months. After surgical treatment but before desensitization, patients experienced significant reductions in SNOT-22 and polyp grade scores. In the first 6 months after aspirin desensitization, patients experienced further significant reductions in SNOT-22 scores, whereas polyp grade remained stable. The improvements in symptom endoscopic scores were preserved throughout the follow-up period after desensitization. No patients required additional sinus surgery. One patient had to discontinue aspirin therapy due to gastrointestinal side effects. No other adverse reactions to aspirin were noted.Aspirin desensitization following ESS appears to be a well-tolerated and effective adjunctive therapy for long-term control of nasal polyposis in patients with AERD.

View details for DOI 10.1177/0194599814545750

View details for Web of Science ID 000342982900008
Long-term sinonasal outcomes of aspirin desensitization in aspirin exacerbated respiratory disease. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Cho, K., Soudry, E., Psaltis, A. J., Nadeau, K. C., McGhee, S. A., Nayak, J. V., Hwang, P. H. 2014; 151 (4): 575-581
Abstract

This study aimed to assess sinonasal outcomes in patients with aspirin exacerbated respiratory disease (AERD) undergoing aspirin desensitization following endoscopic sinus surgery (ESS).Case series with chart review.University hospital.A retrospective review of sinonasal outcomes was conducted for 30 AERD patients undergoing aspirin desensitization and maintenance therapy following ESS. Sinonasal outcomes were prospectively assessed by the Sinonasal Outcomes Test-22 (SNOT-22) and endoscopic polyp grading system. Data were collected preoperatively, 1 and 4 weeks postsurgery (before desensitization), and 1, 6, 12, 18, 24, and 30 months after aspirin desensitization.Twenty-eight of 30 patients (93.3%) successfully completed aspirin desensitization, whereas 2 of 30 (6.7%) were unable to complete desensitization due to respiratory intolerance. Of the 21 patients who successfully completed a minimum of 24 weeks of follow-up, 20 (95.2%) patients demonstrated sustained endoscopic and symptomatic improvement for a median follow-up period of 33 months. After surgical treatment but before desensitization, patients experienced significant reductions in SNOT-22 and polyp grade scores. In the first 6 months after aspirin desensitization, patients experienced further significant reductions in SNOT-22 scores, whereas polyp grade remained stable. The improvements in symptom endoscopic scores were preserved throughout the follow-up period after desensitization. No patients required additional sinus surgery. One patient had to discontinue aspirin therapy due to gastrointestinal side effects. No other adverse reactions to aspirin were noted.Aspirin desensitization following ESS appears to be a well-tolerated and effective adjunctive therapy for long-term control of nasal polyposis in patients with AERD.

View details for DOI 10.1177/0194599814545750

View details for PubMedID 25118195
Abdominal and general adiposity and level of asthma control in adults with uncontrolled asthma. Annals of the American Thoracic Society Lv, N., Xiao, L., Camargo, C. A., Wilson, S. R., Buist, A. S., Strub, P., Nadeau, K. C., Ma, J. 2014; 11 (8): 1218-1224
Abstract

Abdominal adiposity may be an important risk factor for uncontrolled asthma in adults, controlling for general obesity. Whether the relationship, if present, is explained by other factors (e.g., asthma onset age, sex, and/or coexisting conditions) is unclear.To examine whether clinically applicable anthropometric measures of abdominal adiposity--waist circumference and waist-to-height ratio (WHtR)--are related to poorer asthma control in adults with uncontrolled asthma controlling for body mass index (BMI), and whether the relationship (if present) is explained by gastroesophageal reflux disorder (GERD), sleep quality, or obstructive sleep apnea (OSA) or differs by age of asthma onset or sex.Patients aged 18 to 70 years with uncontrolled asthma (n = 90) participated in a 6-month randomized clinical trial.Baseline measures included sociodemographics, standardized anthropometrics, Asthma Control Test (ACT), GERD Symptom Assessment Scale, Pittsburgh Sleep Quality Index, and Berlin Questionnaire for Sleep Apnea. Participants (mean [SD] age, 52 [12] yr) were racially and ethnically diverse, 67% women, and 69% overweight or obese, and 71% reported their age of asthma onset was 12 years or older. Participants had uncontrolled asthma (mean [SD] ACT score, 14.9 [3.7]) and low GERD symptoms score (0.6 [0.4]); 67% reported poor sleep quality, and 42% had a high OSA risk. General linear regression results showed that worse ACT scores were significantly associated with every SD increase in waist circumference (? = -1.03; 95% confidence interval [CI], -1.96 to -0.16; P = 0.02) and waist-to-height ratio (? = -1.16; 95% CI, -2.00 to -0.33; P = 0.008), controlling for sociodemographics. Waist-to-height ratio remained correlated with ACT (? = -2.30; 95% CI, -4.16 to -0.45; P = 0.02) after further adjusting for BMI. The BMI-controlled relationship between WHtR and ACT did not differ by age of asthma onset or sex (P > 0.05 for interactions) and persisted after additional adjustment for GERD, sleep quality, or OSA scores. Poor sleep quality was associated with worse ACT scores (? = -0.87; 95% CI, -1.71 to -0.03; P = 0.045) controlling for waist-to-height ratio, BMI, and sociodemographics.Abdominal adiposity by waist-to-height ratio and poor sleep quality correlated with poorer asthma control in adults with uncontrolled asthma, after controlling for BMI and sociodemographics. These results warrant replication in larger studies of diverse populations. Clinical trial registered with www.clinicaltrials.gov (NCT 01725945).

View details for DOI 10.1513/AnnalsATS.201405-214OC

View details for PubMedID 25343191
Novel protocol including liver biopsy to identify and treat CD8+ T-cell predominant acute hepatitis and liver failure. Pediatric transplantation McKenzie, R. B., Berquist, W. E., Nadeau, K. C., Louie, C. Y., Chen, S. F., Sibley, R. K., Glader, B. E., Wong, W. B., Hofmann, L. V., Esquivel, C. O., Cox, K. L. 2014; 18 (5): 503-509
Abstract

In the majority of children with ALF, the etiology is unknown and liver transplantation is often needed for survival. A patient case prompted us to consider that immune dysregulation may be the cause of indeterminate acute hepatitis and liver failure in children. Our study includes nine pediatric patients treated under a multidisciplinary clinical protocol to identify and treat immune-mediated acute liver injury. Patients with evidence of inflammation and no active infection on biopsy received treatment with intravenous immune globulin and methylprednisolone. Seven patients had at least one positive immune marker before or after treatment. All patients had a CD8+ T-cell predominant liver injury that completely or partially responded to immune therapy. Five of the nine patients recovered liver function and did not require liver transplantation. Three of these patients subsequently developed bone marrow failure and were treated with either immunosuppression or stem cell transplant. This series highlights the importance of this tissue-based approach to diagnosis and treatment that may improve transplant-free survival. Further research is necessary to better characterize the immune injury and to predict the subset of patients at risk for bone marrow failure who may benefit from earlier and stronger immunosuppressive therapy.

View details for DOI 10.1111/petr.12296

View details for PubMedID 24930635
The Potential of Anti-IgE in Food Allergy Therapy. Current treatment options in allergy Manohar, M., Nadeau, K. C. 2014; 1 (2): 145-156
View details for PubMedID 25419508
Epigenetic regulation of asthma and allergic disease ALLERGY ASTHMA AND CLINICAL IMMUNOLOGY Begin, P., Nadeau, K. C. 2014; 10
Abstract

Epigenetics of asthma and allergic disease is a field that has expanded greatly in the last decade. Previously thought only in terms of cell differentiation, it is now evident the epigenetics regulate many processes. With T cell activation, commitment toward an allergic phenotype is tightly regulated by DNA methylation and histone modifications at the Th2 locus control region. When normal epigenetic control is disturbed, either experimentally or by environmental exposures, Th1/Th2 balance can be affected. Epigenetic marks are not only transferred to daughter cells with cell replication but they can also be inherited through generations. In animal models, with constant environmental pressure, epigenetically determined phenotypes are amplified through generations and can last up to 2 generations after the environment is back to normal. In this review on the epigenetic regulation of asthma and allergic diseases we review basic epigenetic mechanisms and discuss the epigenetic control of Th2 cells. We then cover the transgenerational inheritance model of epigenetic traits and discuss how this could relate the amplification of asthma and allergic disease prevalence and severity through the last decades. Finally, we discuss recent epigenetic association studies for allergic phenotypes and related environmental risk factors as well as potential underlying mechanisms for these associations.

View details for DOI 10.1186/1710-1492-10-27

View details for Web of Science ID 000337487700001

View details for PubMedID 24932182

View details for PubMedCentralID PMC4057652
Regulatory T cells and their roles in immune dysregulation and allergy. Immunologic research Pellerin, L., Jenks, J. A., B�gin, P., Bacchetta, R., Nadeau, K. C. 2014; 58 (2-3): 358-368
Abstract

The main function of the immune system is to fight off potential infections, but also to maintain its activity below a level that would trigger self-reactivity. Regulatory T cells (Tregs) such as forkhead box P3(+) (FOXP3) Tregs and type 1 regulatory T cells (Tr1) play an essential role in this active process, using several distinct suppressive mechanisms. A wide range of pathologies have been associated with altered Treg cell function. This is best exemplified by the impact of mutations of genes essential for Treg function and the associated autoimmune syndromes. This review summarizes the main features of different subtypes of Tregs and focuses on the clinical implications of their altered function in human studies. More specifically, we discuss abnormalities affecting FOXP3(+) Tregs and Tr1 cells that will lead to autoimmune manifestations and/or allergic reactions, and the potential therapeutic use of Tregs.

View details for DOI 10.1007/s12026-014-8512-5

View details for PubMedID 24781194
Introduction to the special issue on Stanford Immunology. Immunologic research Jones, P. P., Nadeau, K. C. 2014; 58 (2-3): 161-163
View details for DOI 10.1007/s12026-014-8520-5

View details for PubMedID 24798554
Polycyclic aromatic hydrocarbons, tobacco smoke, and epigenetic remodeling in asthma. Immunologic research Klingbeil, E. C., Hew, K. M., Nygaard, U. C., Nadeau, K. C. 2014; 58 (2-3): 369-373
Abstract

Environmental determinants including aerosolized pollutants such as polycyclic aromatic hydrocarbons (PAHs) and tobacco smoke have been associated with exacerbation and increased incidence of asthma. The influence of aerosolized pollutants on the development of immune dysfunction in asthmatics has been suggested to be mediated through epigenetic remodeling. Genome accessibility and transcription are regulated primarily through DNA methylation, histone modification, and microRNA transcript silencing. Epigenetic remodeling has been shown in studies to be associated with Th2 polarization and associated cytokine and chemokine regulation in the development of asthma. This review will present evidence for the contribution of the aerosolized pollutants PAH and environmental tobacco smoke to epigenetic remodeling in asthma.

View details for DOI 10.1007/s12026-014-8508-1

View details for PubMedID 24760221
Distinct Anti-Cytokine Autoantibody Profile is Likely Driven by Innate Hyperinflammation Among Patients with Primary Immunodeficiency Secondary To Rag Mutations Walter, J. E., Rosen, L. B., Chen, K., Lee, Y., Tirosh, I., Csomos, K., Ujhazi, B., Al-Herz, W., Cowan, M. J., Puck, J., Bleesing, J. J., Malech, H., DeRavin, S., Gennery, A. R., Abraham, R., Butte, M. J., Nadeau, K. C., Sullivan, K. E., Giliani, S., Niehues, T., Schuetz, C., Kuijpers, T., Holland, S. M., Browne, S. K., Notarangelo, L. D. SPRINGER/PLENUM PUBLISHERS. 2014: 353?54
View details for Web of Science ID 000336046800030
Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). journal of allergy and clinical immunology Syed, A., Garcia, M. A., Lyu, S., Bucayu, R., Kohli, A., Ishida, S., Berglund, J. P., Tsai, M., Maecker, H., O'Riordan, G., Galli, S. J., Nadeau, K. C. 2014; 133 (2): 500-510
Abstract

The mechanisms contributing to clinical immune tolerance remain incompletely understood. This study provides evidence for specific immune mechanisms that are associated with a model of operationally defined clinical tolerance.Our overall objective was to study laboratory changes associated with clinical immune tolerance in antigen-induced T cells, basophils, and antibodies in subjects undergoing oral immunotherapy (OIT) for peanut allergy.In a phase 1 single-site study, we studied participants (n = 23) undergoing peanut OIT and compared them with age-matched allergic control subjects (n = 20) undergoing standard of care (abstaining from peanut) for 24 months. Participants were operationally defined as clinically immune tolerant (IT) if they had no detectable allergic reactions to a peanut oral food challenge after 3 months of therapy withdrawal (IT, n = 7), whereas those who had an allergic reaction were categorized as nontolerant (NT; n = 13).Antibody and basophil activation measurements did not statistically differentiate between NT versus IT participants. However, T-cell function and demethylation of forkhead box protein 3 (FOXP3) CpG sites in antigen-induced regulatory T cells were significantly different between IT versus NT participants. When IT participants were withdrawn from peanut therapy for an additional 3 months (total of 6 months), only 3 participants remained classified as IT participants, and 4 participants regained sensitivity along with increased methylation of FOXP3 CpG sites in antigen-induced regulatory T cells.In summary, modifications at the DNA level of antigen-induced T-cell subsets might be predictive of a state of operationally defined clinical immune tolerance during peanut OIT.

View details for DOI 10.1016/j.jaci.2013.12.1037

View details for PubMedID 24636474
FOXP3 Epigenetic Signature To Distinguish Between Thymic- and Peripherally-Derived Regulatory T Cells During In Vivo Induction Of Immune Tolerance Begin, P., Baron, U., Olek, S., Bacchetta, R., Nadeau, K. C. MOSBY-ELSEVIER. 2014: AB137
View details for DOI 10.1016/j.jaci.2013.12.507

View details for Web of Science ID 000330241300480
Urinary Polycyclic Aromatic Hydrocarbon Metabolites and Th2 Immunity In Children Hew, K. M., Walker, A. I., Kohli, A., Syed, A., McDonald-Hyman, C., Li, Z., Sjodin, A., Nadeau, K. C. MOSBY-ELSEVIER. 2014: AB232
View details for DOI 10.1016/j.jaci.2013.12.825

View details for Web of Science ID 000330241301117
A Randomized, Double-Blind, Placebo-Controlled Trial of Omalizumab Combined with Oral Immunotherapy (OIT) in the Treatment of Cow's Milk Allergy (CMA): Safety of Dosing Kim, J. S., Wood, R. A., Lindblad, R., Noone, S. A., Paterakis, M. N., Henning, A., Nadeau, K. C., Spann, K., Sampson, H. A. MOSBY-ELSEVIER. 2014: AB403
View details for DOI 10.1016/j.jaci.2013.12.1067

View details for Web of Science ID 000330241302019
Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). journal of allergy and clinical immunology Syed, A., Garcia, M. A., Lyu, S., Bucayu, R., Kohli, A., Ishida, S., Berglund, J. P., Tsai, M., Maecker, H., O'Riordan, G., Galli, S. J., Nadeau, K. C. 2014; 133 (2): 500-510 e11
View details for DOI 10.1016/j.jaci.2013.12.1037

View details for PubMedID 24636474
Identification of STAT5A and STAT5B Target Genes in Human T Cells. PloS one Kanai, T., Seki, S., Jenks, J. A., Kohli, A., Kawli, T., Martin, D. P., Snyder, M., Bacchetta, R., Nadeau, K. C. 2014; 9 (1)
View details for DOI 10.1371/journal.pone.0086790

View details for PubMedID 24497979
Multiple-allergen oral immunotherapy improves quality of life in caregivers of food-allergic pediatric subjects. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Otani, I. M., B�gin, P., Kearney, C., Dominguez, T. L., Mehrotra, A., Bacal, L. R., Wilson, S., Nadeau, K. 2014; 10 (1): 25-?
View details for DOI 10.1186/1710-1492-10-25

View details for PubMedID 24860608
Atopy Patch Testing for Food Allergies FOOD ALLERGY: ADVERSE REACTIONS TO FOODS AND FOOD ADDITIVES, 5TH EDITION Ta, V., Nadeau, K., Metcalfe, D. D., Sampson, H. A., Simon, R. A., Lack, G. 2014: 289?95
View details for Web of Science ID 000460755400023
Exome sequencing and genome-wide copy number variant mapping reveal novel associations with sensorineural hereditary hearing loss. BMC genomics Haraksingh, R. R., Jahanbani, F., Rodriguez-Paris, J., Gelernter, J., Nadeau, K. C., Oghalai, J. S., Schrijver, I., Snyder, M. P. 2014; 15: 1155-?
Abstract

The genetic diversity of loci and mutations underlying hereditary hearing loss is an active area of investigation. To identify loci associated with predominantly non-syndromic sensorineural hearing loss, we performed exome sequencing of families and of single probands, as well as copy number variation (CNV) mapping in a case-control cohort.Analysis of three distinct families revealed several candidate loci in two families and a single strong candidate gene, MYH7B, for hearing loss in one family. MYH7B encodes a Type II myosin, consistent with a role for cytoskeletal proteins in hearing. High-resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known to be involved in hearing (e.g. GJB6, OTOA, and STRC, encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR = 3.91, 95% CI: 1.62-9.40, p = 1.45 x 10-7).We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the etiology of hearing loss. Our study also demonstrates the challenges of exome sequencing and genome-wide CNV mapping for direct clinical application, and illustrates the need for functional and clinical follow-up as well as curated open-access databases.

View details for DOI 10.1186/1471-2164-15-1155

View details for PubMedID 25528277
Multiple-allergen oral immunotherapy improves quality of life in caregivers of food-allergic pediatric subjects. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Otani, I. M., B�gin, P., Kearney, C., Dominguez, T. L., Mehrotra, A., Bacal, L. R., Wilson, S., Nadeau, K. 2014; 10 (1): 25-?
Abstract

Food allergy (FA) negatively affects quality of life in caregivers of food-allergic children, imposing a psychosocial and economic burden. Oral immunotherapy (OIT) is a promising investigational therapy for FA. However, OIT can be a source of anxiety as it carries risk for allergic reactions. The effect of OIT with multiple food allergens (mOIT) on FA-specific health-related quality of life (HRQL) has never been studied in participants with multiple, severe food allergies. This study is the first to investigate the effects of mOIT on FA-related HRQL in caregivers of pediatric subjects.Caregiver HRQL was assessed using a validated Food Allergy Quality of Life - Parental Burden (FAQL-PB) Questionnaire (J Allergy Clin Immunol 114(5):1159-1163, 2004). Parents of participants in two single-center Phase I clinical trials receiving mOIT (n?=?29) or rush mOIT with anti-IgE (omalizumab) pre-treatment (n?=?11) completed the FAQL-PB prior to study intervention and at 2 follow-up time-points (6�months and 18�months). Parents of subjects not receiving OIT (control group, n?=?10) completed the FAQL-PB for the same time-points.HRQL improved with clinical (change?
View details for DOI 10.1186/1710-1492-10-25

View details for PubMedID 24860608
Identification of STAT5A and STAT5B target genes in human T cells. PloS one Kanai, T., Seki, S., Jenks, J. A., Kohli, A., Kawli, T., Martin, D. P., Snyder, M., Bacchetta, R., Nadeau, K. C. 2014; 9 (1)
Abstract

Signal transducer and activator of transcription (STAT) comprises a family of universal transcription factors that help cells sense and respond to environmental signals. STAT5 refers to two highly related proteins, STAT5A and STAT5B, with critical function: their complete deficiency is lethal in mice; in humans, STAT5B deficiency alone leads to endocrine and immunological problems, while STAT5A deficiency has not been reported. STAT5A and STAT5B show peptide sequence similarities greater than 90%, but subtle structural differences suggest possible non-redundant roles in gene regulation. However, these roles remain unclear in humans. We applied chromatin immunoprecipitation followed by DNA sequencing using human CD4(+) T cells to detect candidate genes regulated by STAT5A and/or STAT5B, and quantitative-PCR in STAT5A or STAT5B knock-down (KD) human CD4(+) T cells to validate the findings. Our data show STAT5A and STAT5B play redundant roles in cell proliferation and apoptosis via SGK1 interaction. Interestingly, we found a novel, unique role for STAT5A in binding to genes involved in neural development and function (NDRG1, DNAJC6, and SSH2), while STAT5B appears to play a distinct role in T cell development and function via DOCK8, SNX9, FOXP3 and IL2RA binding. Our results also suggest that one or more co-activators for STAT5A and/or STAT5B may play important roles in establishing different binding abilities and gene regulation behaviors. The new identification of these genes regulated by STAT5A and/or STAT5B has major implications for understanding the pathophysiology of cancer progression, neural disorders, and immune abnormalities.

View details for DOI 10.1371/journal.pone.0086790

View details for PubMedID 24497979

View details for PubMedCentralID PMC3907443
Safety and feasibility of oral immunotherapy to multiple allergens for food allergy. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology B�gin, P., Winterroth, L. C., Dominguez, T., Wilson, S. P., Bacal, L., Mehrotra, A., Kausch, B., Trela, A., Hoyte, E., O'Riordan, G., Seki, S., Blakemore, A., Woch, M., Hamilton, R. G., Nadeau, K. C. 2014; 10 (1): 1-?
Abstract

Thirty percent of children with food allergy are allergic to more than one food. Previous studies on oral immunotherapy (OIT) for food allergy have focused on the administration of a single allergen at the time. This study aimed at evaluating the safety of a modified OIT protocol using multiple foods at one time.Participants underwent double-blind placebo-controlled food challenges (DBPCFC) up to a cumulative dose of 182�mg of food protein to peanut followed by other nuts, sesame, dairy or egg. Those meeting inclusion criteria for peanut only were started on single-allergen OIT while those with additional allergies had up to 5 foods included in their OIT mix. Reactions during dose escalations and home dosing were recorded in a symptom diary.Forty participants met inclusion criteria on peanut DBPCFC. Of these, 15 were mono-allergic to peanut and 25 had additional food allergies. Rates of reaction per dose did not differ significantly between the two groups (median of 3.3% and 3.7% in multi and single OIT group, respectively; p?=?.31). In both groups, most reactions were mild but two severe reactions requiring epinephrine occurred in each group. Dose escalations progressed similarly in both groups although, per protocol design, those on multiple food took longer to reach equivalent doses per food (median +4 mo.; p?
View details for DOI 10.1186/1710-1492-10-1

View details for PubMedID 24428859
Phase 1 results of safety and tolerability in a rush oral immunotherapy protocol to multiple foods using Omalizumab. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology B�gin, P., Dominguez, T., Wilson, S. P., Bacal, L., Mehrotra, A., Kausch, B., Trela, A., Tavassoli, M., Hoyte, E., O'Riordan, G., Blakemore, A., Seki, S., Hamilton, R. G., Nadeau, K. C. 2014; 10 (1): 7-?
Abstract

Up to 30% of patients with food allergies have clinical reactivity to more than one food allergen. Although there is currently no cure, oral immunotherapy (OIT) is under investigation. Pilot data have shown that omalizumab may hasten the ability to tolerate over 4�g of food allergen protein.To evaluate the safety and dose tolerability of a Phase 1 Single Site OIT protocol using omalizumab to allow for a faster and safe desensitization to multiple foods simultaneously.Participants with multiple food allergies received OIT for up to 5 allergens simultaneously with omalizumab (rush mOIT). Omalizumab was administered for 8 weeks prior to and 8 weeks following the initiation of a rush mOIT schedule. Home reactions were recorded with diaries.Twenty-five (25) participants were enrolled in the protocol (median age 7 years). For each included food, participants had failed an initial double-blind placebo-controlled food challenge at a protein dose of 100�mg or less. After pre-treatment with omalizumab, 19 participants tolerated all 6 steps of the initial escalation day (up to 1250�mg of combined food proteins), requiring minimal or no rescue therapy. The remaining 6 were started on their highest tolerated dose as their initial daily home doses. Participants reported 401 reactions per 7,530 home doses (5.3%) with a median of 3.2 reactions per 100 doses. Ninety-four percent (94%) of reactions were mild. There was one severe reaction. Participants reached their maintenance dose of 4,000�mg protein per allergen at a median of 18 weeks.These phase 1 data demonstrate that rush OIT to multiple foods with 16 weeks of treatment with omalizumab could allow for a fast desensitization in subjects with multiple food allergies. Phase 2 randomized controlled trials are needed to better define safety and efficacy parameters of multi OIT experimental treatments with and without omalizumab.

View details for DOI 10.1186/1710-1492-10-7

View details for PubMedID 24576338
Oral immunotherapy for the treatment of food allergy HUMAN VACCINES & IMMUNOTHERAPEUTICS Begin, P., Chinthrajah, R. S., Nadeau, K. C. 2014; 10 (8): 2295-2302
Abstract

Oral immunotherapy (OIT) is an emerging new therapy for food allergy. With multiple small exploratory trials and some large randomized-controlled phase 2 trials recently published and under way, there is a clear progress and interest toward making this a treatment option for patients suffering from food allergies. However, there are still many questions to be answered and parameters to fine-tune before OIT becomes an accepted option outside of the research setting. This review covers the main milestones in the development of OIT for food allergy and further discusses important specific issues that will have direct impact on its clinical application. More specifically, previous publications showing evidence for the induction of tolerance are specifically reviewed and varying safety, tolerability and efficacy parameters from previous reports are also discussed.

View details for DOI 10.4161/hv.29233

View details for Web of Science ID 000344318300027

View details for PubMedID 25424935
Safety and feasibility of oral immunotherapy to multiple allergens for food allergy. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology B�gin, P., Winterroth, L. C., Dominguez, T., Wilson, S. P., Bacal, L., Mehrotra, A., Kausch, B., Trela, A., Hoyte, E., O'Riordan, G., Seki, S., Blakemore, A., Woch, M., Hamilton, R. G., Nadeau, K. C. 2014; 10 (1): 1-?
View details for DOI 10.1186/1710-1492-10-1

View details for PubMedID 24428859
Phase 1 results of safety and tolerability in a rush oral immunotherapy protocol to multiple foods using Omalizumab. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology B�gin, P., Dominguez, T., Wilson, S. P., Bacal, L., Mehrotra, A., Kausch, B., Trela, A., Tavassoli, M., Hoyte, E., O'Riordan, G., Blakemore, A., Seki, S., Hamilton, R. G., Nadeau, K. C. 2014; 10 (1): 7-?
View details for DOI 10.1186/1710-1492-10-7

View details for PubMedID 24576338
Selective ablation of mast cells or basophils reduces peanut-induced anaphylaxis in mice. journal of allergy and clinical immunology Reber, L. L., Marichal, T., Mukai, K., Kita, Y., Tokuoka, S. M., Roers, A., Hartmann, K., Karasuyama, H., Nadeau, K. C., Tsai, M., Galli, S. J. 2013; 132 (4): 881-888 e11
Abstract

Studies with c-kit mutant mast cell (MC)-deficient mice and antibody-mediated depletion of basophils suggest that both MCs and basophils can contribute to peanut-induced anaphylaxis (PIA). However, interpretation of data obtained by using such approaches is complicated because c-kit mutant mice have several phenotypic abnormalities in addition to MC deficiency and because basophil-depleting antibodies can also react with MCs.We analyzed (1) the changes in the features of PIA in mice after the selective and inducible ablation of MCs or basophils and (2) the possible importance of effector cells other than MCs and basophils in the PIA response.Wild-type and various mutant mice were orally sensitized with peanut extract and cholera toxin weekly for 4 weeks and challenged intraperitoneally with peanut extract 2 weeks later.Peanut-challenged, MC-deficient Kit(W-sh/W-sh) mice had reduced immediate hypothermia, as well as a late-phase decrease in body temperature that was abrogated by antibody-mediated depletion of neutrophils. Diphtheria toxin-mediated selective depletion of MCs or basophils in Mcpt5-Cre;iDTR and Mcpt8(DTR) mice, respectively, and treatment of wild-type mice with the basophil-depleting antibody Ba103 significantly reduced peanut-induced hypothermia. Non-c-kit mutant MC- and basophil-deficient Cpa3-Cre;Mcl-1(fl/fl) mice had reduced but still significant responses to peanut.Inducible and selective ablation of MCs or basophils in non-c-kit mutant mice can significantly reduce PIA, but partial responses to peanut can still be observed in the virtual absence of both cell types. The neutrophilia in Kit(W-sh/W-sh) mice might influence the responses of these mice in this PIA model.

View details for DOI 10.1016/j.jaci.2013.06.008

View details for PubMedID 23915716

View details for PubMedCentralID PMC3794715
In utero arsenic exposure and infant infection in a United States cohort: A prospective study ENVIRONMENTAL RESEARCH Farzan, S. F., Korrick, S., Li, Z., Enelow, R., Gandolfi, A. J., Madan, J., Nadeau, K., Karagas, M. R. 2013; 126: 24-30
Abstract

Arsenic (As), a ubiquitous environmental toxicant, has recently been linked to disrupted immune function and enhanced infection susceptibility in highly exposed populations. In drinking water, as levels above the EPA maximum contaminant level occur in our US study area and are a particular health concern for pregnant women and infants. As a part of the New Hampshire Birth Cohort Study, we investigated whether in utero exposure to As affects risk of infant infections. We prospectively obtained information on 4-month-old infants (n=214) using a parental telephone survey on infant infections and symptoms, including respiratory infections, diarrhea and specific illnesses, as well as the duration and severity of infections. Using logistic regression and Poisson models, we evaluated the association between maternal urinary As during pregnancy and infection risks adjusted for potentially confounding factors. Maternal urinary As concentrations were related to total number of infections requiring a physician visit (relative risk (RR) per one-fold increase in As in urine=1.5; 95% confidence interval (CI)=1.0, 2.1) or prescription medication (RR=1.6; 95% CI=1.1, 2.4), as well as lower respiratory infections treated with prescription medication (RR=3.3; 95% CI=1.2, 9.0). Associations were observed with respiratory symptoms (RR=4.0; 95% CI=1.0, 15.8), upper respiratory infections (RR=1.6; 95% CI=1.0, 2.5), and colds treated with prescription medication (RR=2.3; 95% CI=1.0, 5.2). Our results provide initial evidence that in utero As exposure may be related to infant infection and infection severity and provide insight into the early life impacts of fetal As exposure.

View details for DOI 10.1016/j.envres.2013.05.001

View details for Web of Science ID 000326135200004

View details for PubMedID 23769261

View details for PubMedCentralID PMC3808159
Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Chen, R., Giliani, S., Lanzi, G., Mias, G. I., Lonardi, S., Dobbs, K., Manis, J., Im, H., Gallagher, J. E., Phanstiel, D. H., Euskirchen, G., Lacroute, P., Bettinger, K., Moratto, D., Weinacht, K., Montin, D., Gallo, E., Mangili, G., Porta, F., Notarangelo, L. D., Pedretti, S., Al-Herz, W., Alfahdli, W., Comeau, A. M., Traister, R. S., Pai, S., Carella, G., Facchetti, F., Nadeau, K. C., Snyder, M., Notarangelo, L. D. 2013; 132 (3): 656-?
Abstract

Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects.We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families.We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A (TTC7A) on 3 additional patients with CID-MIA.Through analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA.We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA.

View details for DOI 10.1016/j.jaci.2013.06.013

View details for Web of Science ID 000323612000018

View details for PubMedID 23830146
Food allergy diagnosis and therapy: where are we now? IMMUNOTHERAPY Syed, A., Kohli, A., Nadeau, K. C. 2013; 5 (9): 931-944
Abstract

Food allergy is a growing worldwide epidemic that adversely effects up to 10% of the population. Causes and risk factors remain unclear and diagnostic methods are imprecise. There is currently no accepted treatment for food allergy. Therefore, there is an imminent need for greater understanding of food allergies, revised diagnostics and development of safe, effective therapies. Oral immunotherapy provides a particularly promising avenue, but is still highly experimental and not ready for clinical use.

View details for DOI 10.2217/imt.13.93

View details for Web of Science ID 000323735600007

View details for PubMedID 23998729
Differentiating the roles of STAT5B and STAT5A in human CD4(+) T cells CLINICAL IMMUNOLOGY Jenks, J. A., Seki, S., Kanai, T., Huang, J., Morgan, A. A., Scalco, R. C., Nath, R., Bucayu, R., Wit, J. M., Al-Herz, W., Ramadan, D., Jorge, A. A., Bacchetta, R., Hwa, V., Rosenfeld, R., Nadeau, K. C. 2013; 148 (2): 227-236
Abstract

STAT5A and STAT5B are highly homologous proteins whose distinctive roles in human immunity remain unclear. However, STAT5A sufficiency cannot compensate for STAT5B defects, and human STAT5B deficiency, a rare autosomal recessive primary immunodeficiency, is characterized by chronic lung disease, growth failure and autoimmunity associated with regulatory T cell (Treg) reduction. We therefore hypothesized that STAT5A and STAT5B play unique roles in CD4(+) T cells. Upon knocking down STAT5A or STAT5B in human primary T cells, we found differentially regulated expression of FOXP3 and IL-2R in STAT5B knockdown T cells and down-regulated Bcl-X only in STAT5A knockdown T cells. Functional ex vivo studies in homozygous STAT5B-deficient patients showed reduced FOXP3 expression with impaired regulatory function of STAT5B-null Treg cells, also of increased memory phenotype. These results indicate that STAT5B and STAT5A act partly as non-redundant transcription factors and that STAT5B is more critical for Treg maintenance and function in humans.

View details for DOI 10.1016/j.clim.2013.04.014

View details for Web of Science ID 000322101300009

View details for PubMedID 23773921

View details for PubMedCentralID PMC4169138
USE OF A NOVEL PROTOCOL TO SUCCESSFULLY CHARACTERIZE AND TREAT IMMUNE-MEDIATED ACUTE HEPATITIS AND LIVER FAILURE IN CHILDREN McKenzie, R. B., Berquist, W., Esquivel, C., Nadeau, K., Chen, S., Sibley, R., Cox, K. WILEY-BLACKWELL. 2013: 52
View details for Web of Science ID 000321439600042
DASH for asthma: A pilot study of the DASH diet in not-well-controlled adult asthma CONTEMPORARY CLINICAL TRIALS Ma, J., Strub, P., Lavori, P. W., Buist, S., Camargo, C. A., Nadeau, K. C., Wilson, S. R., Xiao, L. 2013; 35 (2): 55-67
Abstract

This pilot study aims to provide effect size confidence intervals, clinical trial and intervention feasibility data, and procedural materials for a full-scale randomized controlled trial that will determine the efficacy of Dietary Approaches to Stop Hypertension (DASH) as adjunct therapy to standard care for adults with uncontrolled asthma. The DASH diet encompasses foods (e.g., fresh fruit, vegetables, and nuts) and antioxidant nutrients (e.g., vitamins A, C, E, and zinc) with potential benefits for persons with asthma, but it is unknown whether the whole diet is beneficial. Participants (n=90) will be randomized to receive usual care alone or combined with a DASH intervention consisting of 8 group and 3 individual sessions during the first 3months, followed by at least monthly phone consultations for another 3months. Follow-up assessments will occur at 3 and 6months. The primary outcome measure is the 7-item Juniper Asthma Control Questionnaire, a validated composite measure of daytime and nocturnal symptoms, activity limitations, rescue medication use, and percentage predicted forced expiratory volume in 1second. We will explore changes in inflammatory markers important to asthma pathophysiology (e.g., fractional exhaled nitric oxide) and their potential to mediate the intervention effect on disease control. We will also conduct pre-specified subgroup analyses by genotype (e.g., polymorphisms on the glutathione S transferase gene) and phenotype (e.g., atopy, obesity). By evaluating a dietary pattern approach to improving asthma control, this study could advance the evidence base for refining clinical guidelines and public health recommendations regarding the role of dietary modifications in asthma management.

View details for DOI 10.1016/j.cct.2013.04.008

View details for Web of Science ID 000322560900007

View details for PubMedID 23648395
The Use of Epinephrine in Acute Allergic Reaction to Food PEDIATRIC ANNALS Dominguez, T. L., Begin, P., Nadeau, K. C. 2013; 42 (7): 293-295
View details for DOI 10.3928/00904481-20130619-14

View details for Web of Science ID 000322203700019

View details for PubMedID 23805971

View details for PubMedCentralID PMC4161447
The Impact of Food Allergies on Quality of Life PEDIATRIC ANNALS Bacal, L. R., Nadeau, K. C. 2013; 42 (7): 141-145
Abstract

CME EDUCATIONAL OBJECTIVES 1. Recognize and appreciate the impact of food allergies on psychosocial health. 2. List the factors that have been shown to negatively affect health-related quality of life. 3. Understand how physicians can directly help to improve a child's quality of life while living with food allergies. Food allergy is a serious problem affecting a growing number of children worldwide. There is a large body of evidence supporting the detrimental effects that food allergy can have on a child's quality of life. With validated tools, we can identify these children and focus on how to protect, guide, and help them to live a safe life. Recent research articulates how food allergies impact health-related quality of life (HRQL). There are studies reported from the child's perspective, as well as studies reported from the parent's perspective. With the development of validated disease and age-specific questionnaires, researchers can reliably gather data on the psychological aspect of children with food allergies. The purpose of this article is to provide a review of the literature examining the psycho-social impact of food allergies on children. This article was designed to outline suggestions to help physicians care for the whole child - both mind and body.

View details for DOI 10.3928/00904481-20130619-12

View details for Web of Science ID 000322203700005
Diagnosis of Food Allergy PEDIATRIC ANNALS Begin, P., Nadeau, K. C. 2013; 42 (6): 102-109
Abstract

Diagnosis of food allergy can be challenging. Given the limited specificity of available allergy tests, these need to be interpreted in light of pre-test probability that is determined by a careful history. Using likelihood ratios calculated from previous publication may allow a more individualized assessment. This approach is likely to be most useful in patients with low to moderate results, below the 95% positive predictive value for that food. This review covers the diagnostic approach of immunoglobulin E-mediated food allergy. We first focus on the pre-test clinical assessment of a patient with a suspected food allergy. We then compare currently available diagnostic tests and discuss their performance for frequent food allergens. Finally, we conclude with the interpretation of allergy tests in light of the pre-test assessment to determine final probability of food allergy and indications for referral to an allergy specialist for food challenge.

View details for DOI 10.3928/00904481-20130522-10

View details for Web of Science ID 000322201500003

View details for PubMedID 23718238

View details for PubMedCentralID PMC4161456
Use of a Novel Protocol to Successfully Characterize and Treat Immune-Mediated Acute Hepatitis and Liver Failure in Children 13th American Transplant Congress (ATC) McKenzie, R., Berquist, W., Nadeau, K., Chen, S., Sibley, R., Cox, K. WILEY-BLACKWELL. 2013: 49?49
View details for Web of Science ID 000318240300061
Markers of Antigen Presentation and Activation on Eosinophils and T Cells in the Esophageal Tissue of Patients With Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Le-Carlson, M., Seki, S., Abarbanel, D., Quiros, A., Cox, K., Nadeau, K. C. 2013; 56 (3): 257-262
Abstract

Evidence suggests eosinophils may be acting as antigen-presenting cells (APCs) by presenting antigen to T cells. We investigated the surface proteins of eosinophils and T cells in the esophageal biopsies of patients with eosinophilic esophagitis (EoE), patients with gastroesophageal reflux disease (GERD), and healthy controls (HCs).: Subjects were categorized as EoE, GERD, or HC. In esophageal tissue, EG2+ eosinophils were stained for the APC markers, CD40 or CD80, via immunohistochemistry. CD3+ T cells were stained for costimulatory markers, CD40L or CD28, and for activation markers, CD69 or CD134, via immunofluorescence or immunohistochemistry.Eosinophils stained with CD40 and CD80. The number of EG2+CD40+ cells was increased in EoE (mean 19.1�14.8 cells/high-power field [HPF], n=11), compared with GERD (mean 0.13�0.19 cells/HPF, n=5, P<0.01) and HC (mean 0.3�0.7 cells/HPF, n=5, P<0.01). There was an elevation in EG2+CD80+ cells in EoE (mean 18.1�16.2 cells/HPF, n=10), GERD (mean 1.7�2.8 cells/HPF, n=6, P<0.01), or HC (mean 0.8�1.3 cells/HPF, n=6, P<0.01). CD3+ T cells stained with CD40L (not quantified). CD3+ T cells stained with CD28 at elevated levels in EoE (mean 14�8.7 cells/HPF, n=9) versus GERD (mean 3.3�1.2 cells/HPF, n=6, P<0.05) or HC (mean 3.0�3.2 cells/HPF, n=7, P<0.01). The number of CD3+CD69+ cells was highest in EoE (mean 14.8�7.5 cells/HPF, n=6) versus GERD (mean 0.8�0.9 cells/HPF, n=6, P<0.001) or HC (mean 2.7�2.5 cells/HPF, n=6, P<0.001).We show that esophageal eosinophils express CD40 and CD80, and T cells with CD40L, CD28, and CD69. The number of double-stained cells was higher in EoE in comparison to control groups. These data support the hypothesis that eosinophils in EoE may act as APCs, activating T cells.

View details for DOI 10.1097/MPG.0b013e3182758d49

View details for Web of Science ID 000315461400010

View details for PubMedID 23059644
Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis. Journal of clinical immunology Abarbanel, D. N., Seki, S. M., Davies, Y., Marlen, N., Benavides, J. A., Cox, K., Nadeau, K. C., Cox, K. L. 2013; 33 (2): 397-406
Abstract

Vancomycin has been shown to affect tumor necrosis factor-alpha (TNF-?) pathways as an immunomodulator; this is thought to be separate from its function as an antibiotic [1]. Previous studies have shown that oral vancomycin (OV) is an effective treatment for concomitant primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) in children [2, 3]. Since both diseases are associated with immune dysfunction, we hypothesized that vancomycin's therapeutic effect in IBD and PSC occurs through immunomodulation. Therefore, we examined the in vivo immunological changes that occur during OV treatment of 14 children with PSC and IBD. Within 3 months of OV administration, peripheral gamma-glutamyl transpeptidase (GGT) and alanine aminotransferase (ALT) concentrations, white blood cell (WBC) counts, and neutrophil counts normalized from elevated levels before treatment. Patients also demonstrated improved biliary imaging studies, liver biopsies and IBD symptoms and biopsies. Additionally, plasma transforming growth factor beta (TGF-?) levels were increased without concurrent shifts in Th1-or Th2-associated cytokine production. Peripheral levels of CD4?+?CD25hiCD127lo and CD4?+?FoxP3+ regulatory T (Treg) cells also increased in OV-treated PSC?+?IBD patients compared to pretreatment levels. A unique case study shows that the therapeutic effects of OV in the treatment of PSC?+?IBD do not always endure after OV discontinuation, with relapse of PSC associated with a decrease in blood Treg levels; subsequent OV retreatment was then associated with a rise in blood Treg levels and normalization of liver function tests (LFTs). Taken together, these studies support immune-related pathophysiology of PSC with IBD, which is responsive to OV.

View details for DOI 10.1007/s10875-012-9801-1

View details for PubMedID 23054338

View details for PubMedCentralID PMC3565076
Mechanisms of Th2 to Treg Vs Th2 to Th1 in Non Rush Vs Rush Food OIT Lyu, S., Nadeau, K. MOSBY-ELSEVIER. 2013: AB196
View details for DOI 10.1016/j.jaci.2012.12.1369

View details for Web of Science ID 000316550800700
Immunotolerance Mechanisms Depend On High Vs Low Dose of Sublingual Immunotherapy Nadeau, K., Vissamsetti, S. MOSBY-ELSEVIER. 2013: AB196
View details for DOI 10.1016/j.jaci.2012.12.1368

View details for Web of Science ID 000316550800699
Molecular Mechanisms Involved in Dendritic Cell-Dependent Regulatory T Cell Generation During Immunotherapy Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) Garcia, M. A., Nadeau, K. MOSBY-ELSEVIER. 2013: AB127?AB127
View details for Web of Science ID 000316550800456
Efficacy of Oral Immunotherapy and Anti-IgE Antibody-Adjunctive Treatment in Patients with Multiple Food Allergies Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) Dominguez, T. L., Wilson, S. P., Sciancalepore, A., Pineda, D., Mehrotra, A., Rubinstein, S. W., Goldsobel, A. B., Mulligan, M. J., Bocian, R. C., Cummings, N., Nadeau, K. MOSBY-ELSEVIER. 2013: AB93?AB93
View details for Web of Science ID 000316550800339
Multi-Allergen Oral Immunotherapy Improves Quality of Life in Subjects with Food Allergies Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) Otani, I., Dominguez, T. L., Sciancalepore, A., Mehrotra, A., Pineda, D., Nadeau, K. MOSBY-ELSEVIER. 2013: AB58?AB58
View details for Web of Science ID 000316550800209
Bystander Suppression in Food Allergy Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) Motosue, M. S., Dominquez, T., Sciancalepore, A., Pineda, D., Mehrotra, A., Hoyte, L., Nadeau, K. MOSBY-ELSEVIER. 2013: AB92?AB92
View details for Web of Science ID 000316550800336
Exposure to Polycyclic Aromatic Hydrocarbons Is Associated with Higher Levels of Total IgE, Decreased Function of T Regulatory Cells and an Increase of Asthma Occurrence in Children Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) Walker, A. I., Kohli, A., Syed, A., Eisen, E. A., Noth, E. M., Pratt, B., Hammond, S. K., Nadeau, K. MOSBY-ELSEVIER. 2013: AB54?AB54
View details for Web of Science ID 000316550800198
Epigenetically mediated pathogenic effects of phenanthrene on regulatory T cells. Journal of toxicology Liu, J., Zhang, L., Winterroth, L. C., Garcia, M., Weiman, S., Wong, J. W., Sunwoo, J. B., Nadeau, K. C. 2013; 2013: 967029-?
Abstract

Phenanthrene (Phe), a polycyclic aromatic hydrocarbon (PAH), is a major constituent of urban air pollution. There have been conflicting results regarding the role of other AhR ligands 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) and 6-formylindolo [3,2-b]carbazole (FICZ) in modifying regulatory T cell populations (Treg) or T helper (Th)17 differentiation, and the effects of Phe have been understudied. We hypothesized that different chemical entities of PAH induce Treg to become either Th2 or Th17 effector T cells through epigenetic modification of FOXP3. To determine specific effects on T cell populations by phenanthrene, primary human Treg were treated with Phe, TCDD, or FICZ and assessed for function, gene expression, and phenotype. Methylation of CpG sites within the FOXP3 locus reduced FOXP3 expression, leading to impaired Treg function and conversion of Treg into a CD4(+)CD25(lo) Th2 phenotype in Phe-treated cells. Conversely, TCDD treatment led to epigenetic modification of IL-17A and conversion of Treg to Th17 T cells. These findings present a mechanism by which exposure to AhR-ligands mediates human T cell responses and begins to elucidate the relationship between environmental exposures, immune modulation, and initiation of human disease.

View details for DOI 10.1155/2013/967029

View details for PubMedID 23533402
Epigenetically Mediated Pathogenic Effects of Phenanthrene on Regulatory T Cells JOURNAL OF TOXICOLOGY Liu, J., Zhang, L., Winterroth, L. C., Garcia, M., Weiman, S., Wong, J. W., Sunwoo, J. B., Nadeau, K. C. 2013
View details for DOI 10.1155/2013/967029

View details for Web of Science ID 000214720400027
Immunologic Effects of Omalizumab in Children with Severe Refractory Atopic Dermatitis: A Randomized, Placebo-Controlled Clinical Trial INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY Iyengar, S. R., Hoyte, E. G., Loza, A., Bonaccorso, S., Chiang, D., Umetsu, D. T., Nadeau, K. C. 2013; 162 (1): 89-93
Abstract

Background: Severe refractory atopic dermatitis (AD) is a chronic, debilitating condition that is associated with elevated serum immunoglobulin E (IgE) levels. Thymic stromal lymphopoietin (TSLP), thymus and activation-regulated chemokine (TARC) and OX40 ligand (OX40L) are important immunologic factors involved in the pathogenesis of AD. Omalizumab, an anti-IgE antibody indicated for use in allergic asthma, is implicated in regulating allergen presentation by dendritic cells and the T cell response during the effector phases of allergic disease. We investigated if anti-IgE therapy modulates the allergen-specific responses mediated by the TSLP pathway in young patients with severe refractory AD. Methods: This was a randomized, double-blind, placebo-controlled study of 8 patients between the ages of 4 and 22 years (mean = 11.6 years) with severe refractory AD (clinical trials.gov NCT01678092). Serum IgE ranged from 218 to 1,890 (mean = 1,068 IU/ml). Subjects received omalizumab (n = 4) or placebo (n = 4) every 2-4 weeks over 24 weeks using a regimen extrapolated from the package insert. TSLP, TARC, OX40L and other cytokines involved in AD were measured by using cytometric bead arrays. Results: All patients receiving omalizumab had strikingly decreased levels of TSLP, OX40L, TARC (involved in Th2 polarization) and interleukin (IL)-9 compared to placebo. In addition, there was a marked increase in IL-10, a tolerogenic cytokine, in the omalizumab-treated group. Patients on anti-IgE therapy had an improvement in clinical outcomes as measured by the SCORAD system; however, these effects were comparable to improvements in the control group. Conclusions: Anti-IgE therapy with omalizumab decreases levels of cytokines that are involved in Th2 polarization and allergic inflammation, including TSLP, TARC and OX40L.

View details for DOI 10.1159/000350486

View details for Web of Science ID 000322776600013

View details for PubMedID 23816920
Asthma Discordance in Twins Is Linked to Epigenetic Modifications of T Cells PLOS ONE Runyon, R. S., Cachola, L. M., Rajeshuni, N., Hunter, T., Garcia, M., Ahn, R., Lurmann, F., Krasnow, R., Jack, L. M., Miller, R. L., Swan, G. E., Kohli, A., Jacobson, A. C., Nadeau, K. C. 2012; 7 (11)
Abstract

T cells mediate the inflammatory responses observed in asthma among genetically susceptible individuals and have been suspected to be prone to epigenetic regulation. However, these relationships are not well established from past clinical studies that have had limited capacity to control for the effects of variable genetic predisposition and early environmental exposures. Relying on a cohort of monozygotic twins discordant for asthma we sought to determine if epigenetic modifications in T cells were associated with current asthma and explored whether such modifications were associated with second hand smoke exposures. Our study was conducted in a monozygotic twin cohort of adult twin pairs (n?=?21) all discordant for asthma. Regulatory T cell (Treg) and effector T cell (Teff) subsets were assessed for levels of cellular function, protein expression, gene expression and CpG methylation within Forkhead box P3 (FOXP3) and interferon gamma-? (IFN?) loci. Comparisons by asthma and current report of exposure to second hand smoke were made. Treg from asthmatic discordant twins demonstrated decreased FOXP3 protein expression and impaired Treg function that was associated with increased levels of CpG methylation within the FOXP3 locus when compared to their non-asthmatic twin partner. In parallel, Teff from discordant asthmatic twins demonstrated increased methylation of the IFN? locus, decreased IFN? expression and reduced Teff function when compared to Teff from the non-asthmatic twin. Finally, report of current exposure to second hand smoke was associated with modifications in both Treg and Teff at the transcriptional level among asthmatics. The results of the current study provide evidence for differential function of T cell subsets in monozygotic twins discordant for asthma that are regulated by changes in DNA methylation. Our preliminary data suggest exposure to second hand smoke may augment the modified T cell responses associated with asthma.

View details for DOI 10.1371/journal.pone.0048796

View details for Web of Science ID 000312376100014

View details for PubMedID 23226205

View details for PubMedCentralID PMC3511472
CHARACTERIZATION OF AUTOANTIBODY PROFILE AMONG PATIENTS WITH PRIMARY IMMUNODEFICIENCY SECONDARY TO RAG MUTATIONS 15th Biennial Meeting of the European-Society-for-Immunodeficiency (ESID) Walter, J. E., Matthew, D., Lee, Y. N., Recher, M., Patrizi, L., Al-Herz, W., Cowan, M., Puck, J., Bleesing, J., Filipovich, L., Niehues, T., Schuetz, C., DRUCKER, G., Malech, H., De Ravin, S. S., Uzel, G., Facchetti, F., Gennery, A., Alenezi, H. M., Chinen, J., Dbaibo, G., El Ghazali, G., Pasic, S., Chen, K., Nadeau, K., Abraham, R., Giliani, S., Balboni, M., Browne, S., Notarangelo, L. D. SPRINGER/PLENUM PUBLISHERS. 2012: 44?44
View details for Web of Science ID 000308728900079
Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Swamy, R. S., Reshamwala, N., Hunter, T., Vissamsetti, S., Santos, C. B., Baroody, F. M., Hwang, P. H., Hoyte, E. G., Garcia, M. A., Nadeau, K. C. 2012; 130 (1): 215-?
Abstract

Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies.We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens.The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n= 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects.Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG(4) levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4(+)CD25(high)CD127(low)CD45RO(+) forkhead box protein 3 (Foxp3)(+) memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus.The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells.

View details for DOI 10.1016/j.jaci.2012.04.021

View details for Web of Science ID 000306644800030

View details for PubMedID 22677046

View details for PubMedCentralID PMC4161455
Modulation of mTOR Effector Phosphoproteins in Blood Basophils from Allergic Patients JOURNAL OF CLINICAL IMMUNOLOGY Gernez, Y., Tirouvanziam, R., Reshamwala, N., Yu, G., Weldon, B. C., Galli, S. J., Herzenberg, L. A., Nadeau, K. C. 2012; 32 (3): 565-573
Abstract

The mammalian target of rapamycin (mTOR) pathway contributes to various immunoinflammatory processes. Yet, its potential involvement in basophil responses in allergy remains unclear. In this pilot study, we quantified two key mTOR effector phosphoproteins, the eukaryotic initiation factor 4E (peIF4E) and S6 ribosomal protein (pS6rp), in blood basophils from nut allergy patients (NA, N?=?16) and healthy controls (HC, N?=?13). Without stimulation in vitro, basophil peIF4E levels were higher in NA than HC subjects (P?=?0.014). Stimulation with nut (offending) but not chicken / rice (non-offending) extract increased basophil peIF4E and pS6rp levels (+32%, P?=?0.018, and +98%, P?=?0.0026, respectively) in NA but not HC subjects, concomitant with increased surface levels of CD203c and CD63, both known to reflect basophil activation. Pre-treatment with the mTOR inhibitor rapamycin decreased pS6rp and CD203c responses in nut extract-stimulated basophils in NA subjects. Thus, basophil responses to offending allergens are associated with modulation of mTOR effector phosphoproteins.

View details for DOI 10.1007/s10875-012-9651-x

View details for Web of Science ID 000305982100019

View details for PubMedID 22350221
Changes in antigen-specific T-cell number and function during oral desensitization in cow's milk allergy enabled with omalizumab MUCOSAL IMMUNOLOGY Bedoret, D., Singh, A. K., Shaw, V., Hoyte, E. G., HAMILTON, R., DeKruyff, R. H., Schneider, L. C., Nadeau, K. C., Umetsu, D. T. 2012; 5 (3): 267-276
Abstract

Food allergy is a major public health problem, for which there is no effective treatment. We examined the immunological changes that occurred in a group of children with significant cow's milk allergy undergoing a novel and rapid high-dose oral desensitization protocol enabled by treatment with omalizumab (anti-immunoglobulin (Ig)E monoclonal antibodies). Within a week of treatment, the CD4(+) T-cell response to milk was nearly eliminated, suggesting anergy in, or deletion of, milk-specific CD4(+) T cells. Over the following 3 months while the subjects remained on high doses of daily oral milk, the CD4(+) T-cell response returned, characterized by a shift from interleukin-4 to interferon-? production. Desensitization was also associated with reduction in milk-specific IgE and a 15-fold increase in milk-specific IgG4. These studies suggest that high-dose oral allergen desensitization may be associated with deletion of allergen-specific T cells, without the apparent development of allergen-specific Foxp3(+) regulatory T cells.

View details for DOI 10.1038/mi.2012.5

View details for Web of Science ID 000303011300006

View details for PubMedID 22318492
Regulatory T Cell Regulation by STAT5B Kanai, T., Seki, S., Jenks, J., Nadeau, K. C. SPRINGER/PLENUM PUBLISHERS. 2012: 357
View details for Web of Science ID 000302615200034
B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice BLOOD Recher, M., Burns, S. O., de la Fuente, M. A., Volpi, S., Dahlberg, C., Walter, J. E., Moffitt, K., Mathew, D., Honke, N., Lang, P. A., Patrizi, L., Falet, H., Keszei, M., Mizui, M., Csizmadia, E., Candotti, F., Nadeau, K., Bouma, G., Delmonte, O. M., Frugoni, F., Fomin, A. B., Buchbinder, D., Lundequist, E. M., Massaad, M. J., Tsokos, G. C., Hartwig, J., Manis, J., Terhorst, C., Geha, R. S., Snapper, S., Lang, K. S., Malley, R., Westerberg, L., Thrasher, A. J., Notarangelo, L. D. 2012; 119 (12): 2819-2828
Abstract

Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS gene that encodes for a protein (WASp) involved in cytoskeleton organization in hematopoietic cells. Several distinctive abnormalities of T, B, and natural killer lymphocytes; dendritic cells; and phagocytes have been found in WASp-deficient patients and mice; however, the in vivo consequence of WASp deficiency within individual blood cell lineages has not been definitively evaluated. By conditional gene deletion we have generated mice with selective deficiency of WASp in the B-cell lineage (B/WcKO mice). We show that this is sufficient to cause a severe reduction of marginal zone B cells and inability to respond to type II T-independent Ags, thereby recapitulating phenotypic features of complete WASp deficiency. In addition, B/WcKO mice showed prominent signs of B-cell dysregulation, as indicated by an increase in serum IgM levels, expansion of germinal center B cells and plasma cells, and elevated autoantibody production. These findings are accompanied by hyperproliferation of WASp-deficient follicular and germinal center B cells in heterozygous B/WcKO mice in vivo and excessive differentiation of WASp-deficient B cells into class-switched plasmablasts in vitro, suggesting that WASp-dependent B cell-intrinsic mechanisms critically contribute to WAS-associated autoimmunity.

View details for DOI 10.1182/blood-2011-09-379412

View details for Web of Science ID 000302121700019

View details for PubMedID 22302739

View details for PubMedCentralID PMC3327460
Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes CELL Chen, R., Mias, G. I., Li-Pook-Than, J., Jiang, L., Lam, H. Y., Chen, R., Miriami, E., Karczewski, K. J., Hariharan, M., Dewey, F. E., Cheng, Y., Clark, M. J., Im, H., Habegger, L., Balasubramanian, S., O'Huallachain, M., Dudley, J. T., Hillenmeyer, S., Haraksingh, R., Sharon, D., Euskirchen, G., Lacroute, P., Bettinger, K., Boyle, A. P., Kasowski, M., Grubert, F., Seki, S., Garcia, M., Whirl-Carrillo, M., Gallardo, M., Blasco, M. A., Greenberg, P. L., Snyder, P., Klein, T. E., Altman, R. B., Butte, A. J., Ashley, E. A., Gerstein, M., Nadeau, K. C., Tang, H., Snyder, M. 2012; 148 (6): 1293-1307
Abstract

Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here, we present an integrative personal omics profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14 month period. Our iPOP analysis revealed various medical risks, including type 2 diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high-coverage genomic and transcriptomic data, which provide the basis of our iPOP, revealed extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and diseased states by connecting genomic information with additional dynamic omics activity.

View details for DOI 10.1016/j.cell.2012.02.009

View details for PubMedID 22424236
Multiplex meta-analysis of RNA expression to identify genes with variants associated with immune dysfunction JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION Morgan, A. A., Pyrgos, V. J., Nadeau, K. C., Williamson, P. R., Butte, A. J. 2012; 19 (2): 284-288
Abstract

We demonstrate a genome-wide method for the integration of many studies of gene expression of phenotypically similar disease processes, a method of multiplex meta-analysis. We use immune dysfunction as an example disease process.We use a heterogeneous collection of datasets across human and mice samples from a range of tissues and different forms of immunodeficiency. We developed a method integrating Tibshirani's modified t-test (SAM) is used to interrogate differential expression within a study and Fisher's method for omnibus meta-analysis to identify differentially expressed genes across studies. The ability of this overall gene expression profile to prioritize disease associated genes is evaluated by comparing against the results of a recent genome wide association study for common variable immunodeficiency (CVID).Our approach is able to prioritize genes associated with immunodeficiency in general (area under the ROC curve = 0.713) and CVID in particular (area under the ROC curve = 0.643).This approach may be used to investigate a larger range of failures of the immune system. Our method may be extended to other disease processes, using RNA levels to prioritize genes likely to contain disease associated DNA variants.

View details for DOI 10.1136/amiajnl-2011-000657

View details for Web of Science ID 000300768100023

View details for PubMedID 22319178

View details for PubMedCentralID PMC3277634
Oral Immunotherapy and Anti-IgE Antibody-Adjunctive Treatment for Food Allergy IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA Nadeau, K. C., Kohli, A., Iyengar, S., DeKruyff, R. H., Umetsu, D. T. 2012; 32 (1): 111-?
Abstract

One of the most promising therapies for food allergy is oral immunotherapy (OIT), in which small amounts of allergen are administered in increasing amounts, with the immediate goal of desensitization and the long-term goal of tolerance. However, safety and standardization concerns prevent its widespread use, and a subgroup of patients may experience severe allergic reactions. These concerns might be addressed by another promising therapy involving anti-IgE monoclonal antibodies (mAb), which can reduce allergic reactions associated with food administration. A recent pilot study combining anti-IgE mAb with OIT suggests that anti-IgE mAb might improve the safety, rapidity, and efficacy of OIT.

View details for DOI 10.1016/j.iac.2011.11.004

View details for Web of Science ID 000300467200010

View details for PubMedID 22244236
Stat5b (Signal Transducer and Activator of Transcription 5b), Not Stat5a, Is a Critical Modulator of Human Treg Development and Function Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) Jenks, J., Seki, S., Huang, J., Nath, R., Madmedov, M., Hwa, V., Rosenfeld, R., Nadeau, K. C. MOSBY-ELSEVIER. 2012: AB10?AB10
View details for Web of Science ID 000301133400040
Autoimmune regulator (AIRE) contributes to Dectin-1-induced TNF-alpha production and complexes with caspase recruitment domain-containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1 JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Pedroza, L. A., Kumar, V., Sanborn, K. B., Mace, E. M., Niinikoski, H., Nadeau, K., Vasconcelos, D. d., Perez, E., Jyonouchi, S., Jyonouchi, H., Banerjee, P. P., Ruuskanen, O., Condino-Neto, A., Orange, J. S. 2012; 129 (2): 464-U287
Abstract

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a complex immunologic disease caused by mutation of the autoimmune regulator (AIRE) gene. Autoimmunity in patients with APECED syndrome has been shown to result from deficiency of AIRE function in transcriptional regulation of thymic peripheral tissue antigens, which leads to defective T-cell negative selection. Candidal susceptibility in patients with APECED syndrome is thought to result from aberrant adaptive immunity.To determine whether AIRE could function in anticandidal innate immune signaling, we investigated an extrathymic role for AIRE in the immune recognition of ?-glucan through the Dectin-1 pathway, which is required for defense against Candida species.Innate immune signaling through the Dectin-1 pathway was assessed in both PBMCs from patients with APECED syndrome and a monocytic cell line. Subcellular localization of AIRE was assessed by using confocal microscopy.PBMCs from patients with APECED syndrome had reduced TNF-? responses after Dectin-1 ligation but in part used a Raf-1-mediated pathway to preserve function. In the THP-1 human monocytic cell line, reducing AIRE expression resulted in significantly decreased TNF-? release after Dectin-1 ligation. AIRE formed a transient complex with the known Dectin-1 pathway components phosphorylated spleen tyrosine kinase and caspase recruitment domain-containing protein 9�after receptor ligation and localized with Dectin-1 at the cell membrane.AIRE can participate in the Dectin-1 signaling pathway, indicating a novel extrathymic role for AIRE and a defect that likely contributes to fungal susceptibility in patients with APECED syndrome.

View details for DOI 10.1016/j.jaci.2011.08.027

View details for Web of Science ID 000299951700026

View details for PubMedID 21962774
Patient and Parent Perspectives on Quality of Life during Participation in a Study of Rapid Oral Desensitization with Omalizumab Therapy in Patients with Milk Allergy Annual Meeting of American-Academy-of-Allergy-Asthma-Immunology (AAAAI) LeBovidge, J. S., Haskell, S., Borras, I., Hoyte, E., Umetsu, D. T., Nadeau, K. C., Schneider, L. C. MOSBY-ELSEVIER. 2012: AB30?AB30
View details for Web of Science ID 000301133400114
The Effects of CCR9+and CD103+Dendritic Cells on Regulatory T-cells in Food Allergy Annual Meeting of American-Academy-of-Allergy-Asthma-Immunology (AAAAI) Garcia, M. A., Nadeau, K. MOSBY-ELSEVIER. 2012: AB24?AB24
View details for Web of Science ID 000301133400094
The STAT5b Pathway Defect and Autoimmunity. Frontiers in immunology Kanai, T., Jenks, J., Nadeau, K. C. 2012; 3: 234-?
Abstract

The signal transducer and activator of transcription (STAT) 5b is a universal transcription factor that plays key biological roles in allergic diseases, immunodeficiencies, autoimmunities, cancers, hematological diseases, growth disorders, and lung diseases. The identification of distinct pathological manifestations of STAT5b deficiency in humans has highlighted the critical role of the STAT5b pathway. Proper gene transcription at IL-2R ?, FOXP3, Bcl-2, and growth hormone (GH) associated loci are thought to be associated with normal STAT5b transcriptional activity. These genes are thought to play important roles in allergy/autoimmunity, immunodeficiency, cancer/anemia, and growth, respectively. The STAT5A and STAT5B genes are collocated on 17q11. Although these two monomeric proteins exhibit peptide sequence similarities of >90%, it is known through observations of STAT5b deficient subjects that STAT5a and STAT5b are not fully redundant in humans. Patients with STAT5b deficiency have decreased numbers of regulatory CD4(+)CD25(high) T cell (Treg) despite their STAT5a levels being normal. Prior studies on STAT5b deficient subjects have revealed immunological aberrations associated with the following disease phenotype: modest lymphopenia and decreased populations of Treg, ?-? T cells, and natural killer (NK) cells. Most subjects with STAT5b deficiency show severe eczema, and autoimmune disease (juvenile idiopathic arthritis, autoimmune thyroiditis, idiopathic thrombocytic purpura) which are thought to be associated with Treg dysfunction. We will review the likely pathophysiological mechanisms associated with STAT5b deficiency.

View details for DOI 10.3389/fimmu.2012.00234

View details for PubMedID 22912632
The STAT5b pathway defect and autoimmunity FRONTIERS IN IMMUNOLOGY Kanai, T., Jenks, J., Nadeau, K. C. 2012; 3
Abstract

The signal transducer and activator of transcription (STAT) 5b is a universal transcription factor that plays key biological roles in allergic diseases, immunodeficiencies, autoimmunities, cancers, hematological diseases, growth disorders, and lung diseases. The identification of distinct pathological manifestations of STAT5b deficiency in humans has highlighted the critical role of the STAT5b pathway. Proper gene transcription at IL-2R ?, FOXP3, Bcl-2, and growth hormone (GH) associated loci are thought to be associated with normal STAT5b transcriptional activity. These genes are thought to play important roles in allergy/autoimmunity, immunodeficiency, cancer/anemia, and growth, respectively. The STAT5A and STAT5B genes are collocated on 17q11. Although these two monomeric proteins exhibit peptide sequence similarities of >90%, it is known through observations of STAT5b deficient subjects that STAT5a and STAT5b are not fully redundant in humans. Patients with STAT5b deficiency have decreased numbers of regulatory CD4(+)CD25(high) T cell (Treg) despite their STAT5a levels being normal. Prior studies on STAT5b deficient subjects have revealed immunological aberrations associated with the following disease phenotype: modest lymphopenia and decreased populations of Treg, ?-? T cells, and natural killer (NK) cells. Most subjects with STAT5b deficiency show severe eczema, and autoimmune disease (juvenile idiopathic arthritis, autoimmune thyroiditis, idiopathic thrombocytic purpura) which are thought to be associated with Treg dysfunction. We will review the likely pathophysiological mechanisms associated with STAT5b deficiency.

View details for DOI 10.3389/fimmu.2012.00234

View details for Web of Science ID 000209501300229

View details for PubMedCentralID PMC3418548
Secondhand smoke in combination with ambient air pollution exposure is associated with increasedx CpG methylation and decreased expression of IFN-gamma in T effector cells and Foxp3 in T regulatory cells in children CLINICAL EPIGENETICS Kohli, A., Garcia, M. A., Miller, R. L., Maher, C., Humblet, O., Hammond, S. K., Nadeau, K. 2012; 4
Abstract

Secondhand smoke (SHS) and ambient air pollution (AAP) exposures have been associated with increased prevalence and severity of asthma and DNA modifications of immune cells. In the current study, we examined the association between SHS and AAP with DNA methylation and expression of interferon-gamma (IFN-?) and forkhead box protein 3 (Foxp3) in T cell populations.Subjects 7-18?years old were recruited from Fresno (high AAP; n?=?62) and Stanford, CA (low AAP; n?=?40) and divided into SHS-exposed (Fresno: n?=?31, Stanford: n?=?6) and non-SHS-exposed (nSHS; Fresno: n?=?31, Stanford: n?=?34) groups. T cells purified from peripheral blood were assessed for levels of DNA methylation and expression of IFN-? (in effector T cells) or Foxp3 (in regulatory T cells).Analysis showed a significant increase in mean % CpG methylation of IFN-? and Foxp3 associated with SHS exposure (IFN-?: FSHS 62.10%, FnSHS 41.29%, p?
View details for DOI 10.1186/1868-7083-4-17

View details for Web of Science ID 000208830900017

View details for PubMedCentralID PMC3483214
Secondhand smoke in combination with ambient air pollution exposure is associated with increasedx CpG methylation and decreased expression of IFN-? in T effector cells and Foxp3 in T regulatory cells in children. Clinical epigenetics Kohli, A., Garcia, M. A., Miller, R. L., Maher, C., Humblet, O., Hammond, S. K., Nadeau, K. 2012; 4 (1): 17-?
Abstract

Secondhand smoke (SHS) and ambient air pollution (AAP) exposures have been associated with increased prevalence and severity of asthma and DNA modifications of immune cells. In the current study, we examined the association between SHS and AAP with DNA methylation and expression of interferon-gamma (IFN-?) and forkhead box protein 3 (Foxp3) in T cell populations.Subjects 7-18?years old were recruited from Fresno (high AAP; n?=?62) and Stanford, CA (low AAP; n?=?40) and divided into SHS-exposed (Fresno: n?=?31, Stanford: n?=?6) and non-SHS-exposed (nSHS; Fresno: n?=?31, Stanford: n?=?34) groups. T cells purified from peripheral blood were assessed for levels of DNA methylation and expression of IFN-? (in effector T cells) or Foxp3 (in regulatory T cells).Analysis showed a significant increase in mean % CpG methylation of IFN-? and Foxp3 associated with SHS exposure (IFN-?: FSHS 62.10%, FnSHS 41.29%, p?
View details for DOI 10.1186/1868-7083-4-17

View details for PubMedID 23009259
The Safety of Peanut Oral Immunotherapy in Peanut-Allergic Subjects in a Single-Center Trial INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY Yu, G. P., Weldon, B., Neale-May, S., Nadeau, K. C. 2012; 159 (2): 179-182
Abstract

Peanut allergy is the leading cause of food-related anaphylaxis, and accidental exposures are common. Oral immunotherapy (OIT) has been posited as a potential treatment.Patients aged 3-65 years with peanut-specific IgE ?7 kU/l and/or a positive skin prick test with a history of an allergic reaction to peanut were recruited to undergo an OIT protocol. All adverse reactions were recorded by research staff or patients in real time.Twenty-four patients received 6,662 doses. Symptoms were mostly mild (84%), and only 3 severe gastrointestinal reactions required the administration of epinephrine. Abdominal pain was the most common reaction, followed by oropharyngeal and lip pruritus. Respiratory symptoms were rare.In this trial of OIT in adults and children, most reactions were mild.

View details for DOI 10.1159/000336391

View details for Web of Science ID 000305801300011

View details for PubMedID 22678151
Genotype, phenotype, and outcomes of nine patients with T-B plus NK plus SCID PEDIATRIC TRANSPLANTATION Yu, G. P., Nadeau, K. C., Berk, D. R., de Saint Basile, G., Lambert, N., Knapnougel, P., Roberts, J., Kavanau, K., Dunn, E., Stiehm, E. R., Lewis, D. B., Umetsu, D. T., Puck, J. M., Cowan, M. J. 2011; 15 (7): 733-741
Abstract

There are few reports of clinical presentation, genotype, and HCT outcomes for patients with T-B+NK+ SCID. Between 1981 and 2007, eight of 84 patients with SCID who received and/or were followed after HCT at UCSF had the T-B+NK+ phenotype. One additional patient with T-B+NK+ SCID was identified as the sibling of a patient treated at UCSF. Chart reviews were performed. Molecular analyses of IL7R, IL2RG, JAK3, and the genes encoding the CD3 T-cell receptor components ? (CD3D), ? (CD3E), and ? (CD3Z) were carried out. IL7R mutations were documented in four patients and CD3D mutations in two others. Three patients had no defects found. Only two of nine patients had an HLA-matched related HCT donor. Both survived, and neither developed GVHD. Five of seven recipients of haploidentical grafts survived. Although the majority of reported cases of T-B+NK+ SCID are caused by defects in IL7R, CD3 complex defects were also found in this series and should be considered when evaluating patients with T-B+NK+ SCID. Additional genes, mutations in which account for T-B+NK+ SCID, remain to be found. Better approaches to early diagnosis and HCT treatment are needed for patients lacking an HLA-matched related donor.

View details for DOI 10.1111/j.1399-3046.2011.01563.x

View details for Web of Science ID 000296049000020

View details for PubMedID 21883749

View details for PubMedCentralID PMC3196791
Monozygotic Twin Pair Showing Discordant Phenotype for X-linked Thrombocytopenia and Wiskott-Aldrich Syndrome: a Role for Epigenetics? JOURNAL OF CLINICAL IMMUNOLOGY Buchbinder, D., Nadeau, K., Nugent, D. 2011; 31 (5): 773-777
Abstract

Despite our increasing characterization of the molecular basis for many primary immunodeficiency states, significant heterogeneity in clinical and immunological phenotype exists. Epigenetic alterations have been implicated in the pathogenesis of immune dysregulation and may provide a unique paradigm to help us understand the phenotypic heterogeneity in primary immunodeficiency. The occurrence of X-linked thrombocytopenia (XLT) and Wiskott-Aldrich syndrome (WAS) in monozygotic twins is a rare occurrence which allows for the exploration of epigenetic alterations and associated phenotypic heterogeneity. We describe a pair of monozygotic twin brothers with a missense mutation in the WAS gene consistent with reduced expression of the WAS protein, a XLT phenotype, and a good prognosis. Despite this genotype and anticipated mild phenotype in both twins, a discordant phenotype has evolved in which one twin demonstrates asymptomatic thrombocytopenia and the other symptomatic thrombocytopenia, infectious complications, and autoimmunity. Characterization of the potential epigenetic contribution to the spectrum of XLT and WAS is described and the implications of these findings are discussed.

View details for DOI 10.1007/s10875-011-9561-3

View details for Web of Science ID 000296012300005

View details for PubMedID 21710275
T(H)1, T(H)2, and T(H)17 cells instruct monocytes to differentiate into specialized dendritic cell subsets BLOOD Alonso, M. N., Wong, M. T., Zhang, A. L., Winer, D., Suhoski, M. M., Tolentino, L. L., Gaitan, J., Davidson, M. G., Kung, T. H., Galel, D. M., Nadeau, K. C., Kim, J., Utz, P. J., Soederstroem, K., Engleman, E. G. 2011; 118 (12): 3311-3320
Abstract

Monocytes and T helper (T(H)) cells rapidly infiltrate inflamed tissues where monocytes differentiate into inflammatory dendritic cells (DCs) through undefined mechanisms. Our studies indicate that T(H) cells frequently interact with monocytes in inflamed skin and elicit the differentiation of specialized DC subsets characteristic of these lesions. In psoriasis lesions, T(H)1 and T(H)17 cells interact with monocytes and instruct these cells to differentiate into T(H)1- and T(H)17-promoting DCs, respectively. Correspondingly, in acute atopic dermatitis, T(H)2 cells interact with monocytes and elicit the formation of T(H)2-promoting DCs. DC formation requires GM-CSF and cell contact, whereas T(H) subset specific cytokines dictate DC function and the expression of DC subset specific surface molecules. Moreover, the phenotypes of T cell-induced DC subsets are maintained after subsequent stimulation with a panel of TLR agonists, suggesting that T(H)-derived signals outweigh downstream TLR signals in their influence on DC function. These findings indicate that T(H) cells govern the formation and function of specialized DC subsets.

View details for DOI 10.1182/blood-2011-03-341065

View details for Web of Science ID 000295120900018

View details for PubMedID 21813450

View details for PubMedCentralID PMC3179399
Immunophenotyping of Peripheral Eosinophils Demonstrates Activation in Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Tammie Nguyen, T., Gernez, Y., Fuentebella, J., Patel, A., Tirouvanziam, R., Reshamwala, N., Bass, D., Berquist, W. E., Cox, K. L., Kerner, J. A., Nadeau, K. C. 2011; 53 (1): 40-47
Abstract

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by upper gastrointestinal symptoms and the presence of high numbers of eosinophils in the esophagus. Although eosinophils in the esophagus have been found to be activated in subjects with EoE, detailed studies of intracellular signaling pathways involved in the mechanism of activation of eosinophils in EoE have heretofore been limited. The aim of the study was to assess whether any surface molecules or transcription factors are activated in peripheral eosinophils in subjects with EoE.Eosinophils and CD3+ lymphocytes were identified directly from 50 ?L of whole blood of EoE and control subjects. Using Hi-FACS, levels of surface activation markers, including CD66b, and intracellular phosphoepitopes, including phosphorylated forms of signal transducer and activator of transcription (phospho-STAT) 1 and 6, were measured within each cell subset.Levels of surface CD66b as well as levels of intracellular phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were significantly higher for untreated subjects with EoE vs healthy controls (P < 0.05). Levels of phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were lower in subjects with EoE on therapy versus untreated subjects with EoE (P < 0.05).Levels of phospho-STAT1 and phospho-STAT6, transcription factors involved in inflammatory processes, were both significantly higher in peripheral eosinophils from untreated (ie, newly diagnosed) subjects with EoE versus subjects with EoE on therapy, healthy controls. Blood-based measurements of CD66b and phospho-STAT levels in peripheral eosinophils may be beneficial for identifying EoE.

View details for DOI 10.1097/MPG.0b013e318212647a

View details for Web of Science ID 000291925500006

View details for PubMedID 21694534
Rapid oral desensitization in combination with omalizumab therapy in patients with cow's milk allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Nadeau, K. C., Schneider, L. C., Hoyte, L., Borras, I., Umetsu, D. T. 2011; 127 (6): 1622-1624
View details for DOI 10.1016/j.jaci.2011.04.009

View details for Web of Science ID 000291048500045

View details for PubMedID 21546071

View details for PubMedCentralID PMC3396422
STAT5b Deficiency: An Unsuspected Cause of Growth Failure, Immunodeficiency, and Severe Pulmonary Disease JOURNAL OF PEDIATRICS Nadeau, K., Hwa, V., Rosenfeld, R. G. 2011; 158 (5): 701-708
View details for DOI 10.1016/j.jpeds.2010.12.042

View details for Web of Science ID 000289286100005

View details for PubMedID 21414633
Serum amyloid A overrides T-reg anergy via monocyte-dependent and T-reg-intrinsic, SOCS3-associated pathways BLOOD Nguyen, K. D., Macaubas, C., Nadeau, K. C., Phi Truong, T., Yoon, T., Lee, T., Park, J. L., Mellins, E. D. 2011; 117 (14): 3793-3798
Abstract

The acute phase protein serum amyloid A (SAA) has been well characterized as an indicator of inflammation. Nevertheless, its functions in pro versus anti-inflammatory processes remain obscure. Here we provide unexpected evidences that SAA induces the proliferation of the tolerogenic subset of regulatory T cells (T(reg)). Intriguingly, SAA reverses T(reg) anergy via its interaction with monocytes to activate distinct mitogenic pathways in T(reg) but not effector T cells. This selective responsiveness of T(reg) correlates with their diminished expression of SOCS3 and is antagonized by T(reg)-specific induction of this regulator of cytokine signaling. Collectively, these evidences suggest a novel anti-inflammatory role of SAA in the induction of a micro-environment that supports T(reg) expansion at sites of infection or tissue injury, likely to curb (auto)-inflammatory responses.

View details for DOI 10.1182/blood-2010-11-318832

View details for Web of Science ID 000289265500014

View details for PubMedID 21325601

View details for PubMedCentralID PMC3296631
STAT5b deficiency: Lessons from STAT5b gene mutations BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM Hwa, V., Nadeau, K., Wit, J. M., Rosenfeld, R. G. 2011; 25 (1): 61-75
Abstract

Growth hormone (GH) regulates insulin-like growth factor (IGF)-I production primarily through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5b signaling cascade. One of four STAT proteins (STAT1, -3, -5a and -5b) activated by the GH-GHR system, the critical importance of STAT5b in IGF-I production became evident with the identification of homozygous, autosomal recessive STAT5b mutations in patients who presented with severe postnatal growth failure, growth hormone insensitivity syndrome (GHIS) and marked IGF-I deficiency. Unlike GHIS due to GHR mutations, patients carrying STAT5b mutations also presented with chronic pulmonary disease and evidence of perturbations of T-cell homeostasis. At present, no single treatment(s) is available to improve both poor statural growth and immune deficiency. Continued clinical evaluations of patients with STAT5b mutations and elucidating the impact of the mutation on STAT5b structure and function, are important to understanding the pathophysiology of this rare, complex, disease (MIM 245590).

View details for DOI 10.1016/j.beem.2010.09.003

View details for PubMedID 21396575
Pretreatment With Omalizumab Permits Rapid Oral Desensitization For Cow's Milk Allergy National Annual Scientific Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) Nadeau, K. C., Schneider, L. C., Hoyte, E., Borras, I., Umetsu, D. T. MOSBY-ELSEVIER. 2011: AB2?AB2
View details for Web of Science ID 000295846400006
The Effect of Polycyclic Aromatic Hydrocarbons on Aryl Hydrocarbon Receptor and DNA Methyltransferase I Transcription National Annual Scientific Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) Cachola, L., Liu, J., McDonald-Hyman, C., Nadeau, K. MOSBY-ELSEVIER. 2011: AB127?AB127
View details for Web of Science ID 000295846400490
Identification of CCR9+and CD103+Dendritic Cells in Tolerance Protocols for Food Allergy National Annual Scientific Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) Garcia, M. A., Yu, G., Singh, A. K., Longbottom, T., Nadeau, K. C. MOSBY-ELSEVIER. 2011: AB30?AB30
View details for Web of Science ID 000295846400112
Use of Specific IgE and Skin Prick Test to Determine Clinical Reaction Severity. British journal of medicine and medical research Ta, V., Weldon, B., Yu, G., Humblet, O., Neale-May, S., Nadeau, K. 2011; 1 (4): 410-429
Abstract

AIMS: To determine whether specific IgE and skin prick test correlate better in predicting reaction severity during a double-blinded placebo controlled food challenge (DBPCFC) for egg, milk, and multiple tree nut allergens. STUDY DESIGN: Prospective study. PLACE AND DURATION OF STUDY: Department of Pediatrics, Stanford University School of Medicine, August 2009 and ongoing. METHODOLOGY: We examined the reaction severity of twenty-four subjects to nine possible food allergens: milk, egg, almond, cashew, hazelnut, peanut, sesame, pecan and walnut. Specific IgE and SPT were performed before each DBPCFC. DBPCFC results were classified into mild (1), moderate (2), or severe (3) reactions using a modified Bock's criteria. RESULTS: Twenty four subjects underwent a total of 80 DBPCFC. Eighty percent of all DBPCFCs resulted in a positive reaction. A majority, 71%, were classified as mild. No reactions occurred with a SPT of zero mm while three reactions occurred with a negative specific IgE. All reactions were reversible with medication. CONCLUSION: These data suggest that SPT and specific IgE levels are not associated with reaction severity (p<0.64 and 0.27, respectively). We also found that combining specific IgE and SPT improved specificity but did not help to achieve clinically useful sensitivity. For instance, an SPT > 5mm had a sensitivity of 91% and specificity of 50%. Combining SPT > 5mm and IgE > 7 resulted in a reduced sensitivity of 64%. Unexpectedly, a history of anaphylaxis 70% (n=17) was not predictive of anaphylaxis on challenge 4% (n=2).

View details for PubMedID 22993721
Apoptosis and Pediatric Idiopathic Neutropenia CURRENT PEDIATRIC REVIEWS Garcia, M., Jeng, M., Nadeau, K. 2011; 7 (4): 321?28
View details for DOI 10.2174/157339611796892337

View details for Web of Science ID 000434515500010
Basophil CD203c Levels Are Increased at Baseline and Can Be Used to Monitor Omalizumab Treatment in Subjects with Nut Allergy INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY Gernez, Y., Tirouvanziam, R., Yu, G., Ghosn, E. E., Reshamwala, N., Tammie Nguyen, T., Tsai, M., Galli, S. J., Herzenberg, L. A., Herzenberg, L. A., Nadeau, K. C. 2011; 154 (4): 318-327
Abstract

Basophils contribute to anaphylaxis and allergies. We examined the utility of assessing basophil-associated surface antigens (CD11b/CD63/CD123/CD203c/CD294) in characterizing and monitoring subjects with nut allergy.We used flow cytometry to analyze basophils at baseline (without any activation) and after ex vivo stimulation of whole blood by addition of nut or other allergens for 2, 10, and 30 min. We also evaluated whether basophil expression of CD11b/CD63/CD123/CD203c/CD294 was altered in subjects treated with anti-IgE monoclonal antibody (omalizumab) to reduce plasma levels of IgE.We demonstrate that basophil CD203c levels are increased at baseline in subjects with nut allergy compared to healthy controls (13 subjects in each group, p < 0.0001). Furthermore, we confirm that significantly increased expression of CD203c occurs on subject basophils when stimulated with the allergen to which the subject is sensitive and can be detected rapidly (10 min of stimulation, n = 11, p < 0.0008). In 5 subjects with severe peanut allergy, basophil CD203c expression following stimulation with peanut allergen was significantly decreased (p < 0.05) after 4 and 8 weeks of omalizumab treatment but returned toward pretreatment levels after treatment cessation.Subjects with nut allergy show an increase of basophil CD203c levels at baseline and following rapid ex vivo stimulation with nut allergen. Both can be reduced by omalizumab therapy. These results highlight the potential of using basophil CD203c levels for baseline diagnosis and therapeutic monitoring in subjects with nut allergy.

View details for DOI 10.1159/000321824

View details for Web of Science ID 000288529200007

View details for PubMedID 20975283

View details for PubMedCentralID PMC3214954
STAT5b Deficiency: An Unsuspected Cause of Growth Failure, Immunodeficiency, and Severe Pulmonary Disease J Pediatr Nadeau KC, Hwa V, Rosenfeld R 2011; 158 (5): 701-8
Migration of regulatory T cells toward airway epithelial cells is impaired in chronic rhinosinusitis with nasal polyposis CLINICAL IMMUNOLOGY Kim, Y. M., Munoz, A., Hwang, P. H., Nadeau, K. C. 2010; 137 (1): 111-121
Abstract

The pathogenesis of chronic rhinosinusitis with nasal polyposis (CRSwNP) is still unclear. To evaluate the role of regulatory T cells (Treg) in the pathogenesis of nasal polyposis, we tested migration potential of Treg purified from subjects with CRSwNP, CRS without NP and controls. The nasal tissue expressions of FOXP3 were analyzed by means of RT-PCR and double immunohistochemistry. Chemotaxis assays were used to evaluate the migration potential of Treg onto bronchial epithelial cells and primary nasal epithelial cells, and toward chemokines. FOXP3(+)CD3(+) cells frequency and FOXP3 transcript expression in nasal tissue, and migration potentials of Treg toward airway epithelial cells and CCL1 were significantly lower in CRSwNP compared with other groups (P<0.05). These results indicate that migration potential of Treg is decreased in CRSwNP subjects, and this may be one of the reasons why tissue infiltration of Treg was decreased as seen in the immunohistochemistry of nasal polyps from CRSwNP subjects.

View details for DOI 10.1016/j.clim.2010.05.013

View details for Web of Science ID 000282204900013

View details for PubMedID 20598643
Ambient air pollution impairs regulatory T-cell function in asthma JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Nadeau, K., McDonald-Hyman, C., Noth, E. M., Pratt, B., Hammond, S. K., Balmes, J., Tager, I. 2010; 126 (4): 845-U280
Abstract

Asthma is the most frequent chronic disease in children, and children are at high risk for adverse health consequences associated with ambient air pollution (AAP) exposure. Regulatory T (Treg) cells are suppressors of immune responses involved in asthma pathogenesis. Treg-cell impairment is associated with increased DNA methylation of Forkhead box transcription factor 3 (Foxp3), a key transcription factor in Treg-cell activity. Because AAP exposure can induce epigenetic changes, we hypothesized that Treg-cell function would be impaired by AAP, allowing amplification of an inflammatory response.To assess whether exposure to AAP led to hypermethylation of the Foxp3 gene, causing impaired Treg-cell suppression and worsened asthma symptom scores.Children with and without asthma from Fresno, Calif (high pollution, Fresno Asthma Group [FA], n�= 71, and Fresno Non Asthmatic Group, n�= 30, respectively), and from Stanford, Calif (low pollution, Stanford Asthma Group, n�= 40, and Stanford Non Asthmatic Group, n�= 40), were enrolled in a cross-sectional study. Peripheral blood Treg cells were used in functional and epigenetic studies. Asthma outcomes were assessed by Global Initiative in Asthma score.Fresno Asthma Group Treg-cell suppression was impaired and FA Treg-cell chemotaxis were reduced compared with other groups (P�? .05). Treg-cell dysfunction was associated with more pronounced decreases in asthma Global Initiative in Asthma score in FA versus the Stanford Asthma Group. Foxp3 was decreased in FA compared with the Fresno Non Asthmatic Group (P�? .05). FA also contained significantly higher levels of methylation at the Foxp3 locus (P�? .05).Increased exposure to AAP is associated with hypermethylation of the Foxp3 locus, impairing Treg-cell function and increasing asthma morbidity. AAP could play a role in mediating epigenetic changes in Treg cells, which may worsen asthma by an immune mechanism.

View details for DOI 10.1016/j.jaci.2010.08.008

View details for Web of Science ID 000282510000024

View details for PubMedID 20920773
Increased HLA-DR Expression on Tissue Eosinophils in Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Patel, A. J., Fuentebella, J., Gernez, Y., Nguyen, T., Bass, D., Berquist, W., Cox, K., Sibley, E., Kerner, J., Nadeau, K. 2010; 51 (3): 290-294
Abstract

The aim of the study was to investigate whether eosinophils have increased human leukocyte antigen (HLA)-DR expression in subjects with eosinophilic esophagitis (EoE) compared with controls.Patients who were undergoing an upper endoscopy with biopsies for suspected gastroesophageal reflux disease (GERD) or EoE at Lucile Packard Children's Hospital were enrolled. In total, the blood and tissue samples of 10 healthy controls (HC), 11 subjects with GERD, and 10 with EoE were studied. Multiple tissue staining to identify eosinophils (via eosinophil cationic protein-clone EG2) and major histocompatibility complex class II cell surface receptors (via HLA-DR) was performed via immunohistochemistry. The peripheral blood was analyzed using flow cytometry to detect eosinophil HLA-DR expression among these subjects.In the tissue, a greater proportion of eosinophils expressed HLA-DR among the subjects with EoE (mean 0.83 +/- 0.14, n = 9) relative to those with GERD (mean 0.18 +/- 0.19, n = 8, P < 0.01) and HC (mean 0.18 +/- 0.13, n = 6, P < 0.01). In total, 6 participants (4 HC subjects and 2 subjects with GERD) did not have any eosinophils identified on tissue staining and were unable to be included in the present statistical analysis. In the blood, there was no statistically significant difference in eosinophil HLA-DR expression among HC subjects (mean 415 +/- 217, n = 6), subjects with GERD (mean 507 +/- 429, n = 2), and those with EoE (mean 334 +/- 181, n = 6).These data demonstrate that the eosinophils from the esophagus of subjects with EoE have increased HLA-DR expression within this tissue.

View details for DOI 10.1097/MPG.0b013e3181e083e7

View details for Web of Science ID 000281453500008

View details for PubMedID 20639774
Epoprostenol-associated pneumonitis: Diagnostic use of a T-cell proliferation assay JOURNAL OF HEART AND LUNG TRANSPLANTATION Kudelko, K. T., Nadeau, K., Leung, A. N., Liu, J., Haddad, F., Zamanian, R. T., Perez, V. D. 2010; 29 (9): 1071-1075
Abstract

We describe a case of severe drug-induced interstitial pneumonitis in a woman with idiopathic pulmonary arterial hypertension receiving epoprostenol confirmed by a drug T-cell proliferation assay. Proliferation assays were completed in our patient and in a healthy control. Isolated T cells were incubated with CD3-depleted peripheral blood mononuclear cells and then stimulated to proliferate with (3)H-thymidine in the presence of epoprostenol, other prostanoid analogs, and controls. A significant (p < 0.001) T-cell proliferation response occurred in our patient in the presence of epoprostenol alone. There was a trend towards an increased T-cell response to treprostinil but this was statistically insignificant. There was no significant T-cell response to the diluent alone, normal saline, iloprost, or alprostadil. There was no significant proliferation to any drug in the healthy control. Hence, a drug T-cell proliferation assay confirmed that epoprostenol can rarely incite a profound inflammatory response in the pulmonary interstitium.

View details for DOI 10.1016/j.healun.2010.04.023

View details for Web of Science ID 000281494800016

View details for PubMedCentralID PMC2926193
Increased Number of Regulatory T Cells in Children With Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Fuentebella, J., Patel, A., Nguyen, T., Sanjanwala, B., Berquist, W., Kerner, J. A., Bass, D., Cox, K., Hurwitz, M., Huang, J., Nguyen, C., Quiros, J. a., Nadeau, K. 2010; 51 (3): 283-289
Abstract

There are limited data on the role of regulatory T cells (Treg) in the disease pathology of eosinophilic esophagitis (EoE). We tested the differences in Treg in subjects with EoE compared with those with gastroesophageal reflux disease (GERD) and healthy controls (HC).Pediatric patients evaluated by endoscopy were recruited for our study. Participants were categorized into 3 groups: EoE, GERD, and HC. RNA purified from esophageal biopsies were used for real-time quantitative polymerase chain reaction assays and tested for forkhead box P3 (FoxP3) mRNA expression. Treg were identified as CD4+CD25hiCD127lo cells in peripheral blood and as CD3+/FoxP3+cells in esophageal tissue.Forty-eight subjects were analyzed by real-time quantitative polymerase chain reaction: EoE (n = 33), GERD (n = 7), and HC (n = 8). FoxP3 expression was higher by up to 1.5-fold in the EoE group compared with the GERD and HC groups (P < 0.05). Protein levels of FoxP3 in blood and tissue were then investigated in 21 subjects: EoE (n = 10), GERD (n = 6), and HC (n = 5). The percentage of Treg and their subsets in peripheral blood were not significant between groups (P > 0.05). The amount of Treg in esophageal tissue was significantly greater in the EoE group (mean 10.7 CD3+/FoxP3+cells/high power field [HPF]) compared with the other groups (GERD, mean 1.7 CD3+/FoxP3+cells/HPF and HC, mean 1.6 CD3+/FoxP3+cells/HPF) (P < 0.05).We show that Treg are increased in esophageal tissue of EoE subjects compared with GERD and HC subjects. The present study illustrates another possible mechanism involved in EoE that implicates impairment of immune homeostasis.

View details for DOI 10.1097/MPG.0b013e3181e0817b

View details for PubMedID 20639775
Epoprostenol-associated pneumonitis: diagnostic use of a T-cell proliferation assay. journal of heart and lung transplantation Kudelko, K. T., Nadeau, K., Leung, A. N., Liu, J., Haddad, F., Zamanian, R. T., de Jesus Perez, V. 2010; 29 (9): 1071-1075
Abstract

We describe a case of severe drug-induced interstitial pneumonitis in a woman with idiopathic pulmonary arterial hypertension receiving epoprostenol confirmed by a drug T-cell proliferation assay. Proliferation assays were completed in our patient and in a healthy control. Isolated T cells were incubated with CD3-depleted peripheral blood mononuclear cells and then stimulated to proliferate with (3)H-thymidine in the presence of epoprostenol, other prostanoid analogs, and controls. A significant (p < 0.001) T-cell proliferation response occurred in our patient in the presence of epoprostenol alone. There was a trend towards an increased T-cell response to treprostinil but this was statistically insignificant. There was no significant T-cell response to the diluent alone, normal saline, iloprost, or alprostadil. There was no significant proliferation to any drug in the healthy control. Hence, a drug T-cell proliferation assay confirmed that epoprostenol can rarely incite a profound inflammatory response in the pulmonary interstitium.

View details for DOI 10.1016/j.healun.2010.04.023

View details for PubMedID 20627625

View details for PubMedCentralID PMC2926193
Individual Variation in the Germline Ig Gene Repertoire Inferred from Variable Region Gene Rearrangements JOURNAL OF IMMUNOLOGY Boyd, S. D., Gaeta, B. A., Jackson, K. J., Fire, A. Z., Marshall, E. L., Merker, J. D., Maniar, J. M., Zhang, L. N., Sahaf, B., Jones, C. D., Simen, B. B., Hanczaruk, B., Nguyen, K. D., Nadeau, K. C., Egholm, M., Miklos, D. B., Zehnder, J. L., Collins, A. M. 2010; 184 (12): 6986-6992
Abstract

Individual variation in the Ig germline gene repertoire leads to individual differences in the combinatorial diversity of the Ab repertoire, but the study of such variation has been problematic. The application of high-throughput DNA sequencing to the study of rearranged Ig genes now makes this possible. The sequencing of thousands of VDJ rearrangements from an individual, either from genomic DNA or expressed mRNA, should allow their germline IGHV, IGHD, and IGHJ repertoires to be inferred. In addition, where previously mere glimpses of diversity could be gained from sequencing studies, new large data sets should allow the rearrangement frequency of different genes and alleles to be seen with clarity. We analyzed the DNA of 108,210 human IgH chain rearrangements from 12 individuals and determined their individual IGH genotypes. The number of reportedly functional IGHV genes and allelic variants ranged from 45 to 60, principally because of variable levels of gene heterozygosity, and included 14 previously unreported IGHV polymorphisms. New polymorphisms of the IGHD3-16 and IGHJ6 genes were also seen. At heterozygous loci, remarkably different rearrangement frequencies were seen for the various IGHV alleles, and these frequencies were consistent between individuals. The specific alleles that make up an individual's Ig genotype may therefore be critical in shaping the combinatorial repertoire. The extent of genotypic variation between individuals is highlighted by an individual with aplastic anemia who appears to lack six contiguous IGHD genes on both chromosomes. These deletions significantly alter the potential expressed IGH repertoire, and possibly immune function, in this individual.

View details for DOI 10.4049/jimmunol.1000445

View details for Web of Science ID 000278516700047

View details for PubMedID 20495067
Human Basophils: New Mechanisms Of Action And Role In Food Allergy 66th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) Gernez, Y., Tirouvanziam, R., Yu, G., Reshamwala, N., Tsai, M., GALLI, S. J., Herzenberg, L. A., Nadeau, K. C. MOSBY-ELSEVIER. 2010: AB86?AB86
View details for Web of Science ID 000280204100339
Epigenetic Modifications of Foxp3 Locus are Associated with Asthma in Children exposed to High Levels of Ambient Air Pollution 66th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) McDonald-Hyman, C., Tager, I., Nadeau, K. MOSBY-ELSEVIER. 2010: AB356?AB356
View details for Web of Science ID 000280204100932
Bradykinin Inhibitors in Hereditary Angioedema J Angioedema Nelson K, Nadeau KC 2010; 1 (1): 27-30
Mechanistic Studies of Tolerance in sublingual innmunotherapy (SLIT) patients with Dermatophagoides farinae and Timothy grass allergy 10th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Reshamwala, N., Swamy, R., Berquist, S., Nguyen, T., Hoyte, E., Vissamsetti, S., Sivagnanasundaram, A., Saper, V., Hwang, P., Moss, R., Nadeau, K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: S65?S65
View details for DOI 10.1016/j.clim.2010.03.199

View details for Web of Science ID 000277953700183
Transcription Factors as Disease Indicators in Eosinophilic Esophagitis 10th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Nguyen, T., Gernez, Y., Fuentella, J., Patel, A., Tirouvanziam, R., Reshamwala, N., Saper, V., Bass, D., Berquist, W., Kerner, J., Nadeau, K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: S81?S82
View details for DOI 10.1016/j.clim.2010.03.246

View details for Web of Science ID 000277953700230
Ambient Air Pollution Impairs Regulatory T-Cell Function in Asthma. J Allergy Clin Immunol Nadeau KC, Hyman-McDonald C, Hammond K, Balmes J, Tager I 2010; 126 (4): 845-852
Increased Number of Regulatory T Cells in Children with Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutri Fuentebella J, Patel A, Nguyen T, Sanjanwala B, Berquist W, Kerner KA, Bass D, Cox K, Hurwitz M, Hung J, Nguyen C, Quiros JA, Nadeau KC 2010; 51 (3): 283-9
Epoprostenol-Associated Pneumonitis: Diagnostic Use of a T Cell Proliferation Assay J Heart Lung Transplant Kudelko KT, De Jesus Perez V, Jaddad F, Zamanian RG, Nadeau KC, Leung A, Liu J 2010; 29 (9): 1071-5
Increased HLA-DR Expression on Tissue Eosinophils in Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutr Patel AJ, Fuentebella J, Gernez Y, Nguyen T, Bass D, Berquist W, Cox K, Sibley E, Kerner J, Nadeau KC 2010; 51 (3): 290-4
TSLP directly impairs pulmonary Treg function: association with aberrant tolerogenic immunity in asthmatic airway. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Nguyen, K. D., Vanichsarn, C., Nadeau, K. C. 2010; 6 (1): 4-?
Abstract

Even though thymic stromal lymphopoietin (TSLP) has been implicated in the development of allergic inflammation, its influence on immune tolerance mediated by regulatory T cells (Treg) have not been explored. We aimed to dissect the influence of TSLP on immunosuppressive activities of Treg and its potential consequences in human allergic asthma.In vitro culture system was utilized to study the effects of TSLP on human Treg. The functional competency of pulmonary Treg from a cohort of 15 allergic asthmatic, 15 healthy control, and 15 non-allergic asthmatic subjects was also evaluated by suppression assays and flow cytometric analysis.Activated pulmonary Treg expressed TSLP-R and responded to TSLP-mediated activation of STAT5. TSLP directly and selectively impaired IL-10 production of Treg and inhibited their suppressive activity. In human allergic asthma, pulmonary Treg exhibited a significant decrease in suppressive activity and IL-10 production compared to healthy control and non-allergic asthmatic counterparts. These functional alterations were associated with elevated TSLP expression in bronchoalveolar lavage fluid (BAL) of allergic asthmatic subjects. Furthermore, allergic asthmatic BAL could suppress IL-10 production by healthy control pulmonary Treg in a TSLP-dependent manner.These results provide the first evidences for a direct role of TSLP in the regulation of suppressive activities of Treg. TSLP mediated inhibition of Treg function might present a novel pathologic mechanism to dampen tolerogenic immune responses in inflamed asthmatic airway.

View details for DOI 10.1186/1710-1492-6-4

View details for PubMedID 20230634

View details for PubMedCentralID PMC3161393
Eotaxin and FGF enhance signaling through an extracellular signal-related kinase (ERK)-dependent pathway in the pathogenesis of Eosinophilic esophagitis. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Huang, J. J., Joh, J. W., Fuentebella, J., Patel, A., Nguyen, T., Seki, S., Hoyte, L., Reshamwala, N., Nguyen, C., Quiros, A., Bass, D., Sibley, E., Berquist, W., Cox, K., Kerner, J., Nadeau, K. C. 2010; 6 (1): 25-?
Abstract

Eosinophilic esophagitis (EoE) is characterized by the inflammation of the esophagus and the infiltration of eosinophils into the esophagus, leading to symptoms such as dysphagia and stricture formation. Systemic immune indicators like eotaxin and fibroblast growth factor were evaluated for possible synergistic pathological effects. Moreover, blood cells, local tissue, and plasma from EoE and control subjects were studied to determine if the localized disease was associated with a systemic effect that correlated with presence of EoE disease.Real-time polymerase chain reaction from peripheral blood mononuclear cells (PBMC), immunohistochemistry from local esophageal biopsies, fluid assays on plasma, and fluorescence-activated cell sorting on peripheral blood cells from subjects were used to study the systemic immune indicators in newly diagnosed EoE (n = 35), treated EoE (n = 9), Gastroesophageal reflux disease (GERD) (n = 8), ulcerative colitis (n = 5), Crohn's disease (n = 5), and healthy controls (n = 8).Of the transcripts tested for possible immune indicators, we found extracellular signal-regulated kinase (ERK), Bcl-2, bFGF (basic fibroblast growth factor), and eotaxin levels were highly upregulated in PBMC and associated with disease presence of EoE. Increased FGF detected by immunohistochemistry in esophageal tissues and in PBMC was correlated with low levels of pro-apoptotic factors (Fas, Caspase 8) in PBMC from EoE subjects. Plasma-derived bFGF was shown to be the most elevated and most specific in EoE subjects in comparison to healthy controls and disease control subjects.We describe for the first time a possible mechanism by which increased FGF is associated with inhibiting apoptosis in local esophageal tissues of EoE subjects as compared to controls. Eotaxin and FGF signaling pathways share activation through the ERK pathway; together, they could act to increase eosinophil activation and prolong the half-life of eosinophils in local tissues of the esophagus in EoE subjects.

View details for DOI 10.1186/1710-1492-6-25

View details for PubMedID 20815913

View details for PubMedCentralID PMC2976489
Measurement and Clinical Monitoring of Human Lymphocyte Clonality by Massively Parallel V-D-J Pyrosequencing SCIENCE TRANSLATIONAL MEDICINE Boyd, S. D., Marshall, E. L., Merker, J. D., Maniar, J. M., Zhang, L. N., Sahaf, B., Jones, C. D., Simen, B. B., Hanczaruk, B., Nguyen, K. D., Nadeau, K. C., Egholm, M., Miklos, D. B., Zehnder, J. L., Fire, A. Z. 2009; 1 (12)
Abstract

The complex repertoire of immune receptors generated by B and T cells enables recognition of diverse threats to the host organism. In this work, we show that massively parallel DNA sequencing of rearranged immune receptor loci can provide direct detection and tracking of immune diversity and expanded clonal lymphocyte populations in physiological and pathological contexts. DNA was isolated from blood and tissue samples, a series of redundant primers was used to amplify diverse DNA rearrangements, and the resulting mixtures of barcoded amplicons were sequenced using long-read ultra deep sequencing. Individual DNA molecules were then characterized on the basis of DNA segments that had been joined to make a functional (or nonfunctional) immune effector. Current experimental designs can accommodate up to 150 samples in a single sequence run, with the depth of sequencing sufficient to identify stable and dynamic aspects of the immune repertoire in both normal and diseased circumstances. These data provide a high-resolution picture of immune spectra in normal individuals and in patients with hematological malignancies, illuminating, in the latter case, both the initial behavior of clonal tumor populations and the later suppression or re-emergence of such populations after treatment.

View details for DOI 10.1126/scitranslmed.3000540

View details for Web of Science ID 000277263200001

View details for PubMedID 20161664

View details for PubMedCentralID PMC2819115
Impaired IL-10-dependent Induction of Tolerogenic Dendritic Cells by CD4(+)CD25(hi)CD127(lo/-) Natural Regulatory T Cells in Human Allergic Asthma AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Nguyen, K. D., Vanichsarn, C., Nadeau, K. C. 2009; 180 (9): 823-833
Abstract

Tolerogenic dendritic cells and natural regulatory T cells have been implicated in the process of infectious tolerance in human allergic asthma. However, the significance of the influence of natural regulatory T cells on tolerogenic dendritic cells in the disease has not been investigated.We aimed to characterize the mechanism of induction of the tolerogenic phenotype in circulating blood dendritic cells by allergic asthmatic natural regulatory T cells.The study was performed in a cohort of 21 subjects with allergic asthma, 21 healthy control subjects, and 21 subjects with nonallergic asthma. We cultured blood dendritic cells with natural regulatory T cells to study the induction of tolerogenic dendritic cells. Flow cytometry and proliferation assays were employed to analyze phenotype and function of dendritic cells as well as IL-10 production from natural regulatory T cells.Dendritic cells cultured with natural regulatory T cells up-regulated IL-10, down-regulated costimulatory molecules, and stimulated the proliferation of CD4(+)CD25(-) effector T cells less potently. Allergic asthmatic natural regulatory T cells were significantly less efficient in inducing this tolerogenic phenotype of dendritic cells compared with healthy control and nonallergic asthmatic counterparts. Furthermore, this defective function of natural regulatory T cells was associated with their decreased IL-10 expression, disease severity, and could be reversed by oral corticosteroid therapy.These results provided the first evidences of impaired induction of tolerogenic dendritic cells mediated by natural regulatory T cells in human allergic asthma.

View details for DOI 10.1164/rccm.200905-0761OC

View details for Web of Science ID 000271215500006

View details for PubMedID 19679691
Neonatal Alloimmune Thrombocytopenia and Neutropenia Associated With Maternal Human Leukocyte Antigen Antibodies PEDIATRIC BLOOD & CANCER Gramatges, M. M., Fani, P., Nadeau, K., Pereira, S., Jeng, M. R. 2009; 53 (1): 97-99
Abstract

Neonatal thrombocytopenia or neutropenia may result from passive transfusion of maternally derived antibodies. Antibodies against platelet antigens are commonly associated with neonatal alloimmune thrombocytopenia (NAIT), and anti-neutrophil antibodies are frequently identified in alloimmune neonatal neutropenia (ANN). Combined alloimmune cytopenias in the newborn are rarely reported; even fewer reports document human leukocyte antigen (HLA) antibodies as a potential cause of neonatal thrombocytopenia or neutropenia. We describe neutropenia and thrombocytopenia in a newborn associated with markedly elevated maternal HLA antibodies in the absence of anti-neutrophil or anti-platelet antibodies to highlight consideration of HLA antibodies in the pathogenesis of ANN and NAIT.

View details for DOI 10.1002/pbc.21979

View details for PubMedID 19229975
Regulatory T cell dysfunction in subjects with common variable immunodeficiency complicated by autoimmune disease CLINICAL IMMUNOLOGY Yu, G. P., Chiang, D., Song, S. J., Hoyte, E. G., Huang, J., Vanishsarn, C., Nadeau, K. C. 2009; 131 (2): 240-253
Abstract

Approximately 25% of subjects with common variable immunodeficiency (CVID) develop autoimmune disease. We analyzed T cell subsets, specifically regulatory T cells along with B cell subsets to determine whether there were changes in regulatory T cells which would correlate with the autoimmune disease clinical phenotype in CVID subjects. We hypothesized that regulatory T cell (CD4+CD25hiCD127lo) suppressive function would be impaired in CVID subjects with autoimmune disease. Using purified, sorted Treg from CVID subjects (n=14) and from healthy controls (HC, n=5) in standard suppression assays, we found the suppressive function of Treg from CVID subjects with autoimmune disease (CVID w/ AI, n=8) to be significantly attenuated compared to CVID subjects with no autoimmune disease (CVID w/o AI, n=6) and to HC (n=5). A number of proteins associated with Treg function were decreased in expression as detected through immunofluorescent antibody via flow cytometry (mean fluorescence intensity (MFI) of FoxP3, Granzyme A, XCL1, pSTAT5, and GITR in Treg was significantly lower (by up to 3 fold) in CVID w/ AI compared to CVID w/o AI and HC. Furthermore, a statistically significant correlation was found between intracellular MFI of FoxP3, Granzyme A, and pSTAT5 in Treg and the degree of Treg dysfunction. These results suggest that attenuation of Treg function is associated with autoimmune disease in CVID subjects and may contribute to autoimmune pathogenesis.

View details for DOI 10.1016/j.clim.2008.12.006

View details for Web of Science ID 000265420000007

View details for PubMedID 19162554
Selective deregulation in chemokine signaling pathways of CD4(+)CD25(hi)CD127(lo/-) regulatory T cells in human allergic asthma JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Nguyen, K. D., Vanichsarn, C., Fohner, A., Nadeau, K. C. 2009; 123 (4): 933-939
Abstract

CD4+CD25(hi)CD127(lo)/(-) regulatory T cells have been suggested to be critical regulators of inflammatory processes in allergic asthma. Recent studies reported a selective decrease in the frequency of regulatory T cells in the bronchoalveolar lavage fluid of allergic asthmatic (AA) subjects, prompting the possibility of defective recruitment of these cells to the airway in response to chemokines produced during asthmatic inflammation.This study aimed to characterize the chemotactic profile of circulating regulatory T cells in AA subjects in response to chemokines abundantly produced in airway inflammation, such as CCL1, CCL17, and CCL22.The study was performed in a cohort of 26 AA, 16 healthy control, and 16 non-AA subjects. We used chemotaxis assays to evaluate cell migration, flow cytometry to examine chemokine receptor expression, and phospho-ELISA to study consequent signaling pathways in regulatory T cells.Regulatory T cells, but not CD4+CD25(-)T cells, from AA subjects showed decreased chemotactic responses, specifically to CCL1, in comparison with their healthy control and non-AA counterparts. Decreased CCL1-mediated chemotaxis in AA regulatory T cells was associated with decreased phosphorylation of protein kinase B (AKT), a protein involved in chemokine intracellular signaling. Furthermore, the decreased chemotactic response to CCL1 in AA regulatory T cells significantly correlated with asthma severity and decreased pulmonary function in AA subjects.These results provide the first evidence of dysfunction in the chemokine signaling pathway in AA regulatory T cells.

View details for DOI 10.1016/j.jaci.2008.11.037

View details for Web of Science ID 000265058600023

View details for PubMedID 19152963
Identifying Eosinophilic Esophagitis through Evaluation of Plasma Biomarkers 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology Joh, J., Huang, J., Nguyen, T., Vishwaanath, N., Patel, A., Fuentebella, J., Saper, V., Kerner, J., Cox, K., Berquist, W., Nadeau, K. MOSBY-ELSEVIER. 2009: S169?S169
View details for Web of Science ID 000263596301118
Natural Regulatory T Cell Dysfunction in Subjects with Common Variable Immunodeficiency Complicated by Autoimmune Disease is associated with activation of the AkT-mTOR pathway 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology Yu, G. P., Berquist, S. W., Huang, J. J., Martinez, J., Hoyte, E. G., Vanichsarn, C. T., Nadeau, K. C. MOSBY-ELSEVIER. 2009: S264?S264
View details for Web of Science ID 000263596301497
Correlation of Phenotypic Expression of Milk Sensitivity in Young Patients by the Simultaneous Determination of IgE to Whole Milk Extract and Milk Specific Allergenic Proteins 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology Saper, V., Innerst, D., Nadeau, K., Hoyte, E., Vanichsarn, C., Zychlinsky, E. MOSBY-ELSEVIER. 2009: S30?S30
View details for Web of Science ID 000263596300112
T Lymphocytes and Its Subsets in Transplanted Small Bowel Treated with Alemtuzumab (Campath-1H) Proc XI Int Small Bowel Transplant Sym Fuentebella J, Seki S, Nadeau KC, Castillo RO 2009; Dec: 37-42
Enhanced Expression of CD66b on Peripheral Blood Granulocytes in Eosinophilic Esophagitis Nguyen, T., Gernez, Y., Fuentebella, J., Patel, A., Herzenberg, L., Tirouvanziam, R., Nadeau, K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2009: S120?S121
View details for DOI 10.1016/j.clim.2009.03.356

View details for Web of Science ID 000266342300348
Selective Deregulation in Chemokine Signaling Pathways of CD4+CD25hiCD127lo/-Regulatory T Cells in Human Allergic Asthma Nguyen, K., Nadeau, K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2009: S7
View details for DOI 10.1016/j.clim.2009.03.013

View details for Web of Science ID 000266342300011
T lymphocytes and Its Subsets in Transplanted Small Bowel Treated with Alemtuzumab (Campath-1H) 11th International Symposium on Small Bowel Transplant Fuentebella, J., Seki, S., Nadeau, K., Castillo, R. O. MEDIMOND S R L. 2009: 42?47
View details for Web of Science ID 000303378800008
Idiopathic neutropenia of childhood is associated with Fas/FasL expression CLINICAL IMMUNOLOGY Nadeau, K. C., Callejas, A., Wong, W. B., Joh, J. W., Cohen, H. J., Jeng, M. R. 2008; 129 (3): 438-447
Abstract

Idiopathic neutropenia (IN) in children is characterized by decreased neutrophil counts (<1500/microl), can be acute or chronic (greater than 6 months duration). The pathophysiology is not well understood; therefore, potential mechanisms of pediatric IN were investigated. An increase in Fas transcripts in neutrophils of IN patients compared to age-matched healthy control (HC) neutrophils was observed (p<0.005). Increased expression of Fas protein was found in IN neutrophils, while Fas surface expression on other immune cells was similar. Plasma from acute IN patients had higher protein levels of soluble FasL than chronic IN patients. When HC neutrophils were incubated in plasma from IN patients, greater rates of apoptosis were observed. Biochemical studies suggest the apoptotic factor(s) in plasma is heat-sensitive, non-IgG, and 12-50 kD protein. Addition of anti-sFasL blocking antibodies to patient plasma caused a statistically significant decrease in neutrophil apoptosis. These studies show that the Fas/FasL pathway could be associated with neutrophil apoptosis in childhood IN.

View details for DOI 10.1016/j.clim.2008.08.006

View details for PubMedID 18819843
XCL1 enhances regulatory activities of CD4(+)CD25(high)CD127(low/-) T cells in human allergic asthma JOURNAL OF IMMUNOLOGY Nguyen, K. D., Fohner, A., Booker, J. D., Dong, C., Krensky, A. M., Nadeau, K. C. 2008; 181 (8): 5386-5395
Abstract

Chemokine-mediated recruitment of regulatory cell subsets to the airway during inflammation and enhancement of their activities are potential strategies for therapeutic development in allergic asthma (AA). In this study, we aim to explore the role of XCL1, a chemokine associated with immune suppression and allergy, on CD4(+)CD25(high)CD127(low/-) regulatory T cell (Treg) function in AA. Flow cytometry and PCR analysis showed a reduction in XCL1 and XCR1 expression in AA Treg compared with healthy control and nonallergic asthmatic counterparts. This reduction in XCL1 expression was associated with the suboptimal regulatory function of Treg in AA. Interestingly, incubation with recombinant human XCL1 significantly increased Treg-mediated suppression and cytotoxicity by up-regulating expression of XCL1 and chief effector molecules of Treg function. Altogether, these results suggest an association between dysregulated XCL1 expression and reduced Treg activities in AA, as well as a potential role of XCL1 in reversing defective Treg function in the disease.

View details for Web of Science ID 000260025300030

View details for PubMedID 18832695
Increased cytotoxicity of CD4(+) invariant NKT cells against CD4(+)CD25(hi)CD127(lo/-) regulatory T cells in allergic asthma EUROPEAN JOURNAL OF IMMUNOLOGY Nguyen, K. D., Vanichsarn, C., Nadeau, K. C. 2008; 38 (7): 2034-2045
Abstract

CD4+CD25(hi)CD127(lo/-) regulatory T cells (Treg) have been implicated in the resolution of asthma-associated inflammation while the opposite role of CD4+ invariant NKT (iNKT) cells has been the subject of recent investigations. Studies here focused on mechanisms of interaction between CD4+ iNKT cells and Treg to further explore their roles in allergic asthma (AA). Flow cytometry analysis revealed a significant increase in the expression of the natural cytotoxicity receptors NKp30 and NKp46 by CD4+ iNKT cells in AA subjects compared to healthy controls (HC) and non-allergic asthmatics (NA). Subsequent intracellular staining showed that CD4+ iNKT cells also expressed higher levels of granzyme B and perforin in AA than HC. In in vitro killing assays, AA CD4+ iNKT cells selectively killed autologous Treg, but not CD4+CD25- T cells, more potently than HC and NA counterparts. This increased cytotoxicity positively correlated with asthma severity and granzyme B/perforin expression of CD4+ iNKT cells. Furthermore, it could be abrogated by either inhibition of the granzyme B-/perforin-dependent cell death pathway or oral corticosteroid administration. Altogether, these findings suggest that increased cytotoxicity of CD4+ iNKT cells against Treg might contribute to dysfunctional cellular interactions in AA.

View details for DOI 10.1002/eji.200738082

View details for Web of Science ID 000257826300027

View details for PubMedID 18581330
A novel mutation associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY Bhui, R. D., Lewis, D. B., Nadeau, K. C. 2008; 100 (2): 169-169
View details for Web of Science ID 000253136500012

View details for PubMedID 18320920
Safety of omalizumab treatment in children (> 4 years) with high serum IgE and severe atopic dermatitis and food allergy 64th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology Iyengar, S. R., Hoyte, E. G., Loza, A., Bonaccorso, S., Umetsu, D. T., Nadeau, K. C. MOSBY-ELSEVIER. 2008: S32?S32
View details for Web of Science ID 000253426400126
Altered phosphorylated signal transducer and activator of transcription profile of CD4(+)CD161(+) T cells in asthma: Modulation by allergic status and oral corticosteroids JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Gernez, Y., Tirouvanziam, R., Nguyen, K. D., Herzenberg, L. A., Krensky, A. M., Nadeau, K. C. 2007; 120 (6): 1441-1448
Abstract

Asthma is a complex immunologic disorder linked to altered cytokine signaling.We tested whether asthmatic patients showed any change in cytokine-dependent signal transducer and activator of transcription (STAT) levels, focusing on the central/effector-memory CD4(+)CD161(+) subset, which represents 15% to 25% of circulating T cells.We quantified intracellular levels of active phosphorylated STAT (phospho-STAT) 1, 3, 5, and 6 by means of flow cytometry, without any activation or expansion.Baseline phospho-STAT1 and phospho-STAT6 levels were increased in CD4(+)CD161(+) T cells from asthmatic patients compared with those from healthy control subjects (by 10- and 8-fold, respectively). This asthma-associated alteration was both subset specific because no change was seen in CD4(+)CD161(-)CD25(+) (regulatory T cells) and CD4(+)CD161(-)CD25(-) subsets and isoform specific because phospho-STAT5 and phospho-STAT3 levels were unchanged. Among asthmatic patients, phospho-STAT1 and phospho-STAT6 levels correlated negatively with each other, suggesting antagonistic regulation. Oral corticosteroid (OCS) treatment significantly decreased phospho-STAT6 and IL-4 levels but not phospho-STAT1 levels. Disease parameters showing significant correlations with phospho-STAT1, phospho-STAT6, or both included age at onset, plasma IgE levels, and levels of the T(H)2 cytokines IL-4 and IL-10 and the T(H)1 cytokine IL-2. Overall, combined phospho-STAT1 and phospho-STAT6 measurements showed excellent predictive value for identifying (1) asthmatic patients versus healthy control subjects, (2) allergic versus nonallergic asthmatic patients, and (3) asthmatic patients taking versus those not taking OCSs.Baseline changes in phospho-STAT1 and phospho-STAT6 levels in blood CD4(+)CD161(+) T cells identify asthmatic patients and mirror their allergic status and response to OCSs.These results confirm the pathologic importance of activated STAT1 and STAT6 in asthma and suggest their potential use as clinical biomarkers.

View details for DOI 10.1016/j.jaci.2007.08.012

View details for Web of Science ID 000251653800029

View details for PubMedID 17919711

View details for PubMedCentralID PMC2679255
Role of Fas/FasL pathway in pediatric idiopathic neutropenia 49th Annual Meeting of the American-Society-of-Hematology Joh, J. W., Callejas, A., Wong, W., Cohen, H. J., Nadeau, K., Jeng, M. AMER SOC HEMATOLOGY. 2007: 966A?967A
View details for Web of Science ID 000251100804328
Lymphotactin improves treg function in asthmatics via the STAT5 pathway 7th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Fohner, A., Nguyen, K., Krensky, A. M., Nadeau, K. C. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2007: S77?S77
View details for DOI 10.1016/j.clim.2007.03.397

View details for Web of Science ID 000247137200200
Identification of specific chemokines and apoptosis molecules in pediatric idiopathic neutropenia. 48th Annual Meeting of the American-Society-of-Hematology Callejas, A., Nadeau, K., Bakshi, K., Wong, W., Carroll, T., Lau, K., Yang, Y., Schilling, J., Clayberger, C., Krensky, A., Jeng, M. AMER SOC HEMATOLOGY. 2006: 40B?40B
View details for Web of Science ID 000242440400132
Cutting edge: Decreased accumulation and regulatory function of CD4(+)CD25(high) T cells in human STAT 5b deficiency JOURNAL OF IMMUNOLOGY Cohen, A. C., Nadeau, K. C., Tu, W., Hwa, V., Dionis, K., Bezrodnik, L., Teper, A., Gaillard, M., Heinrich, J., Krensky, A. M., Rosenfeld, R. G., Lewis, D. B. 2006; 177 (5): 2770-2774
Abstract

We show that STAT5b is important for the in vivo accumulation of CD4+ CD25(high) T cells with regulatory cell function. A patient homozygous for a missense A630P STAT5b mutation displayed immune dysregulation and decreased numbers of CD4+ CD25(high) T cells. STAT5b(A630P/A630P) CD4+ CD25(high) T cells had low expression of forkhead box P3 and an impaired ability to suppress the proliferation of or to kill CD4+ CD25- T cells. Expression of CD25, a component of the high-affinity IL-2R, was also reduced in response to IL-2 or after in vitro propagation. The impact of the STAT5b mutation was selective in that IL-2-mediated up-regulation of the common gamma-chain cytokine receptor and perforin, and activation-induced expressions of CD154 and IFN-gamma were normal. These results indicate that STAT5b propagates an important IL-2-mediated signal for the in vivo accumulation of functional regulatory T cells.

View details for Web of Science ID 000240002800007

View details for PubMedID 16920911
Lgl1 is suppressed in oxygen toxicity animal models of bronchopulmonary dysplasia and normalizes during recovery in air PEDIATRIC RESEARCH Nadeau, K., Jankov, R. P., Tanswell, A. K., Sweezey, N. B., Kaplan, F. 2006; 59 (3): 389-395
Abstract

Bronchopulmonary dysplasia (BPD), a major cause of morbidity in premature infants, is characterized by arrest of lung growth and inhibited alveologenesis. We had earlier cloned late-gestation lung 1 (LGL1), a glucocorticoid (GC)-induced, developmentally regulated gene in lung mesenchyme, and showed that reduced levels of late-gestation lung 1 protein (lgl1) inhibit lung branching. Maximal fetal expression of LGL1 is concordant with the onset of alveolar septation, suggesting an additional role for lgl1 in alveologenesis. At postnatal d 7, during the period of maximal septation in postnatal rat lung, lgl1 concentrates at the tips of budding secondary alveolar septa. We studied two models of impaired postnatal alveologenesis generated by exposure of newborn rats to 60% O2 for 2 wk or 95% O2 for 1 wk. A profound decrease of lgl1 expression with oxygen exposure was observed in both animal models. Animals exposed to 95% O2 for 1 wk recovered in air over a 3-wk period, associated with normalization of lgl1 levels. Changes in lung levels of alpha-actin (a marker of myofibroblast differentiation associated with alveologenesis) and the mesenchymal marker vimentin were significant but less marked. Our findings support a role for lgl1 in postnatal lung development. We speculate that deficiency of lgl1 contributes to the arrested alveolar partitioning observed in BPD and that recovery is associated with normalization of lgl1 levels.

View details for DOI 10.1203/01.pdr.0000198819.81785.f1

View details for Web of Science ID 000235626700009

View details for PubMedID 16492977
Outcomes in twelve T-B+Nk+ SCID patients treated with HSCT. 6th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Yu, G., Nadeau, K., Berk, D., Jun, I., Tsao, G., Lewis, D., Krensky, A., Umetsu, D., Mort, C. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2006: S135?S136
View details for DOI 10.1016/j.clim.2006.04.319

View details for Web of Science ID 000237924300361
Decreased generation and function of CD4+CD25(hi) T regulatory cells in human STAT5b deficiency. Cohen, A., Nadeau, K., Tu, W., Hwa, V., Dionis, K., Bezrodnik, L., Teper, A., Gaillard, M., Heinrich, J., Krensky, A., Rosenfeld, R., Lewis, D. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2006: S135
View details for DOI 10.1016/j.clim.2006.04.318

View details for Web of Science ID 000237924300360
Decreased generation and function of CD4+CD25(hi) T regulatory cells in human STAT5b deficiency. Cleary, A., Nadeau, K., Tu, W. W., Hwa, Dionis, K. Y., Bezrodnik, L., Teper, A., Gaillard, M., Heinrich, J. J., Krensky, A. M., Rosenfeld, R. G., Lewis, D. B. AMER SOC HEMATOLOGY. 2005: 227A
View details for Web of Science ID 000233426001237
Successful conversion from conventional immunosuppression to anti-CD154 monoclonal antibody costimulatory molecule blockade in rhesus renal allograft recipients Annual Meeting of the American-Society-of-Transplantation Cho, C. S., Burkly, L. C., Fechner, J. H., Kirk, A. D., Oberley, T. D., Dong, Y. C., Brunner, K. G., Peters, D., Tenhoor, C. N., Nadeau, K., Yagci, G., Ishido, N., Schultz, J. M., Tsuchida, M., Hamawy, M. M., Knechtle, S. J. LIPPINCOTT WILLIAMS & WILKINS. 2001: 587?97
Abstract

Several conventional forms of immunosuppression have been shown to antagonize the efficacy of anti-CD154 monoclonal antibody- (mAb) based costimulatory molecule blockade immunotherapy. Our objective was to determine if allograft recipients treated with a conventional immunosuppressive regimen could be sequentially converted to anti-CD154 mAb monotherapy without compromising graft survival.Outbred juvenile rhesus monkeys underwent renal allotransplantation from MHC-disparate donors. After a 60-day course of triple therapy immunosuppression with steroids, cyclosporine, and mycophenolate mofetil, monkeys were treated with: (1) cessation of all immunosuppression (control); (2) seven monthly doses of 20 mg/kg hu5C8 (maintenance), or; (3) 20 mg/kg hu5C8 on posttransplant days 60, 61, 64, 71, 79, and 88 followed by five monthly doses (induction+maintenance). Graft rejection was defined by elevation in serum creatinine>1.5 mg/dl combined with histologic evidence of rejection.Graft survival for the three groups were as follows: group 1 (control): 70, 75, >279 days; group 2 (maintenance): 83, 349, >293 days, and; group 3 (induction+maintenance): 355, >377, >314 days. Acute rejection developing in two of four monkeys after treatment with conventional immunosuppression was successfully reversed with intensive hu5C8 monotherapy.Renal allograft recipients can be successfully converted to CD154 blockade monotherapy after 60 days of conventional immunosuppression. An induction phase of anti-CD154 mAb appears to be necessary for optimal conversion. Therefore, although concurrent administration of conventional immunosuppressive agents including steroids and calcineurin inhibitors has been shown to inhibit the efficacy of CD154 blockade, sequential conversion from these agents to CD154 blockade appears to be effective.

View details for Web of Science ID 000170968400006

View details for PubMedID 11544416
Inhibition of CD40 ligand (CD154) in the treatment of factor VIII inhibitors. Haematologica Ewenstein, B. M., Hoots, W. K., Lusher, J. M., DiMichele, D., White, G. C., Adelman, B., Nadeau, K. 2000; 85 (10): 35-39
Abstract

The development of persistent, high titer inhibitors represents a serious complication of the treatment of patients with severe hemophilia A. Elimination of these inhibitory antibodies is usually attempted through repeated administration of high doses of factor VIII. Such regimens are costly, time-consuming and often fail when the inhibitor is of very high titer or of longstanding duration. A potential alternative approach to inhibit the production of antifactor VIII antibodies is blockade of the T-cell/B-cell collaboration that is required to generate humoral responses. One cognate receptor pair that is required for T-cell-dependent B-cell activation consists of CD40, which is expressed on B-lymphocytes and other antigen presenting cells, and CD40 ligand (CD40L, CD154), which is transiently expressed on activated T-cells. To determine whether blockade of the CD40-CD40L pathway can inhibit the production of anti-factor VIII antibodies, a clinical study has been designed in which patients with hemophilia A and a high titer inhibitor (> 10 BU) receive monthly exposures to factor VIII in the presence of a humanized mouse monoclonal antibody to human CD40L (hu5c8*). Subjects must be between the ages of 5 and 60 years old and be HIV seronegative. To date, three subjects have received at least three doses of hu5c8 at the initial protocol dose of 10 mg/kg. Preliminary results suggest that anti-CD40L inhibition may be effective in blocking anamnestic responses to factor VIII in some patients. It remains to be determined whether this effect will persist and whether patients may eventually become tolerant to factor VIII in the absence of hu5c8 co-administration.

View details for PubMedID 11187868
Renal allograft protection with losartan in Fisher -> Lewis rats: Hemodynamics, macrophages, and cytokines KIDNEY INTERNATIONAL Ziai, F., Nagano, H., Kusaka, M., Coito, A. J., Troy, J. L., Nadeau, K. C., Rennke, H. G., Tilney, N. L., BRENNER, B. M., Mackenzie, H. S. 2000; 57 (6): 2618-2625
Abstract

We sought to assess the effects of angiotensin receptor blockade on glomerular hypertension, macrophage recruitment, and cytokine expression, all of which contribute to the development of chronic graft injury in this model.The effects of treatment with the specific angiotensin II type 1 (AT1) receptor antagonist, losartan, were assessed over 24 weeks in F344-->LEW rats (LOS, N = 9) versus vehicle-treated F344-->LEW controls (CON, N = 9).UprotV rose progressively in CON (from 7.0 +/- 2.9 to 41 +/- 17 mg/day at 24 wk) but remained at baseline in LOS (4.2 +/- 0.6 to 9.4 +/- 1.3 mg/day, P < 0.05 vs. CON). Glomerular capillary pressure (PGC) was increased in CON (71 +/- 1 mm Hg at week 20), but remained within the normal range in LOS rats (54 +/- 2 mm Hg, P < 0.05). Glomerulosclerosis averaged 0.3 +/- 0.2% in LOS versus 4 +/- 2% in CON rats (P < 0.05). Tubulointerstitial injury was minimal in both LOS and CON rats (+). The overexpression of renal cortical cytokine mRNA levels for the monocyte chemoattractants, monocyte chemoattractant protein-1 (MCP-1) and RANTES, as well as interleukin-1, inducible nitric oxide synthase, and transforming growth factor-beta, assessed by competitive reverse transcription-polymerase chain reaction, was suppressed in LOS versus CON rats at 20 weeks. Macrophage and T-cell numbers were decreased, and MCP-1, RANTES, and intercellular adhesion molecule-1 staining in the graft, identified by immunohistochemistry, were attenuated in LOS versus CON rats.The renoprotective effects of losartan in F344-->LEW rats were associated with lowered PGC, inhibition of macrophage chemoattractants and recruitment, and suppression of macrophage-associated cytokines at 20 weeks. These findings suggest that chronic allograft injury in F344-->LEW rats is, to a large extent, mediated by angiotensin II-dependent mechanisms and that these involve glomerular hemodynamics, macrophages, and macrophage-associated cytokines.

View details for Web of Science ID 000087346100044

View details for PubMedID 10844632
Cloning and characterization of the two enzymes responsible for trypanothione biosynthesis in Crithidia fasciculata JOURNAL OF BIOLOGICAL CHEMISTRY Tetaud, E., Manai, F., Barrett, M. P., Nadeau, K., Walsh, C. T., Fairlamb, A. H. 1998; 273 (31): 19383-19390
Abstract

Protozoa of the order Kinetoplastida differ from other organisms in their ability to conjugate glutathione (gamma-Glu-Cys-Gly) and spermidine to form trypanothione (N1,N8-bis(glutathionyl)spermidine), which is involved in maintaining intracellular thiol redox and in defense against oxidants. In this study, the genes from Crithidia fasciculata, Cf-GSS and Cf-TRS, which encode, respectively, glutathionylspermidine synthetase (EC 6.3.1.8) and trypanothione synthetase (EC 6.3.1.9) have been cloned and expressed. The deduced amino acid sequence of both Cf-GSS and Cf-TRS share 50% sequence similarity with the Escherichia coli glutathionylspermidine synthetase/amidase. Both genes are present as single copies in the C. fasciculata genome. When expressed in E. coli and Saccharomyces cerevisiae, neither protein was present in an active soluble form. However, thiol analysis of S. cerevisiae demonstrated that cells transformed with the Cf-GSS gene contained substantial amounts of glutathionylspermidine, whereas cells expressing both the Cf-GSS and Cf-TRS genes contained glutathionylspermidine and trypanothione, confirming that these genes encode the functional glutathionylspermidine and trypanothione synthetases from C. fasciculata. The translation products of Cf-GSS and Cf-TRS show significant homology to the amidase domain present in E. coli glutathionylspermidine synthetase, which can catalyze both synthesis and degradation of glutathionylspermidine. Glutathionylspermidine synthetase isolated from C. fasciculata was found to possess a similar amidase activity.

View details for Web of Science ID 000075125200007

View details for PubMedID 9677355
Effects of explosive brain death on cytokine activation of peripheral organs in the rat TRANSPLANTATION Takada, M., Nadeau, K. C., Hancock, W. W., Mackenzie, H. S., SHAW, G. D., Waaga, A. M., Chandraker, A., Sayegh, M. H., Tilney, N. L. 1998; 65 (12): 1533-1542
Abstract

The success rate of transplanted organs from brain-dead cadaver donors is consistently inferior to that of living sources. As cadaver and living unrelated donors are equally genetically disparate with a given recipient, the difference must lie within the donor himself and/or the effects of organ preservation and storage. We have hypothesized that irreversible central nervous system injury may up-regulate proinflammatory mediators and cell surface molecules in peripheral organs to be engrafted, making them more prone to host inflammatory and immunological responses.Rats undergoing surgically induced acutely increased intracranial pressure (explosive brain death) were followed for 6 hr. Their peripheral tissues were examined by reverse transcriptase polymerase chain reaction and immunohistology, serum factors were assessed by enzyme-linked immunosorbent assay, and the influence of inflammatory molecules in the blood stream was determined by cross-circulation experiments with normal animals.mRNA expression of both lymphocyte- and macrophage-associated products increased dramatically in all tissues. Similar factors in serum were coincidentally increased; these were shown to be active in vivo by cross-circulation with normal animals. The organs of all control groups, including animals with important ischemic injury and with hemorrhagic shock, were negative. Up-regulation of MHC class I and II antigens and the co-stimulatory molecule B7 suggests increased immunogenicity of the peripheral organs. These changes could be inhibited by: (i) administration of a recombinant soluble P-selectin glycoprotein ligand-Ig, a P- and E-selectin antagonist; and (ii) a fusion protein, cytotoxic T lymphocyte antigen 4-Ig, which blocks B7-mediated T-cell co-stimulation.Activation of peripheral organs following explosive brain death may be caused by various interrelated events, including the effects of massive acute central injury, hypotension, and circulating factors. Almost complete suppression of these changes could be produced by biological agents. Such interventions, if reproducible in humans, could improve the quality of organs from "marginal" donors, broadening the criteria for donor acceptance.

View details for Web of Science ID 000074557600001

View details for PubMedID 9665067
Late blockade of T cell costimulation interrupts progression of experimental chronic allograft rejection JOURNAL OF CLINICAL INVESTIGATION Chandraker, A., Azuma, H., Nadeau, K., Carpenter, C. B., Tilney, N. L., Hancock, W. W., Sayegh, M. H. 1998; 101 (11): 2309-2318
Abstract

Early blockade of T cell-costimulatory activation pathways prevents development of experimental chronic allograft rejection. Ongoing T cell recognition of alloantigen and activation may also play an important role in progression of chronic rejection, but definitive evidence is lacking. We used the fusion protein CTLA4Ig to block CD28-B7 T cell costimulation late after the onset of initial graft injury. Using the F334 into LEW rat model of chronic renal allograft rejection, transplant recipients were treated with a 10-d course of cyclosporine, and a subgroup received a single injection of CTLA4Ig at 8 wk after transplant. Functionally, CTLA4Ig administration prevented development of progressive proteinuria (14.3+/-4.1 mg/24 h versus 41.0+/-12.0 mg/24 h at 24 wk after transplant, P < 0.05). Histologically, graft mononuclear cell infiltration, glomerular hypertrophy, focal and segmental glomerulosclerosis, and intimal vascular hyperplasia were all attenuated in CTLA4Ig-treated animals. Lastly, reverse transcriptase-PCR and immunohistologic studies showed a significant reduction in the intragraft expression of key products of T cell and macrophage activation, and upregulation of what have recently been termed as "protective" genes, including the bcl family members, Bcl-2 and Bcl-xL, and hemoxygenase. Our data are the first to demonstrate that blocking T cell-costimulatory activation late after transplantation, after initial graft injury, prevents progression of chronic allograft rejection supporting the hypothesis that ongoing T cell recognition of alloantigen and activation are key mediators of ongoing chronic allograft rejection.

View details for Web of Science ID 000074165900003

View details for PubMedID 9616202
Influence of initial antigen-independent events on acute allograft rejection: Inhibition by a soluble P-selectin ligand and low-dose cyclosporine in combination International Congress on Immunosuppression Kusaka, M., Nadeau, K. C., Takada, M., Nagano, H., SHAW, G. D., Tilney, N. L. ELSEVIER SCIENCE INC. 1998: 1027?28
View details for Web of Science ID 000074150800039

View details for PubMedID 9636414
Infection-associated macrophage activation accelerates chronic renal allograft rejection in rats TRANSPLANTATION Nagano, H., Nadeau, K. C., Kusaka, M., Heeman, U. W., Tilney, N. L. 1997; 64 (11): 1602-1605
Abstract

The influence of infection-associated cellular activation on chronic rejection of kidney grafts was assessed in an established rat model by administration of lipopolysaccharide (LPS), an endotoxin and a potent stimulator of various cell populations including mononuclear cells and renal epithelial cells.Lewis recipients of F344 kidneys were treated with low-dose cyclosporine (1.5 mg/kg/day x 10 days). Animals with well-functioning grafts received a single dose of LPS (2 mg in 1 ml of NaCl, intraperitoneally) at 4 or 8 weeks after engraftment. Untreated control rats, which later experienced chronic rejection, were given 1 ml of NaCl.Administration of LPS during the early quiescent phase of chronic rejection accelerated the chronic process, functionally (proteinuria), morphologically, immunohistologically, and by reverse-transcriptase polymerase chain reaction as compared with untreated controls. Infiltration of macrophages and their associated factors was especially affected.As the later events of chronic rejection seem to be mediated primarily by macrophages and their products, administration of LPS accelerated the tempo and activity of these cells in the development of chronic rejection. These findings may explain the clinical observation that infection may be an important risk factor for chronic allograft rejection.

View details for Web of Science ID 000071034100018

View details for PubMedID 9415565
Prevention of late renal changes after initial ischemia/reperfusion injury by blocking early selectin binding TRANSPLANTATION Takada, M., Nadeau, K. C., SHAW, G. D., Tilney, N. L. 1997; 64 (11): 1520-1525
Abstract

Increasing clinical evidence suggests that delayed initial function secondary to ischemia/reperfusion injury alone, and particularly in combination with early episodes of acute rejection, reduces kidney allograft survival over time.We investigated changes developing over the long term following a standardized ischemia/reperfusion insult in a Lewis rat model. The left kidney was isolated in a uninephrectomized host and cooled, and the pedicle was clamped for 45 min. Animals were followed for 48 weeks after initial renal injury. Organs were removed serially (4, 8, 16, 24, 32, 40, and 48 weeks) for immunohistology and reverse transcriptase polymerase chain reaction.Progressive proteinuria developed after 8 weeks. By immunohistology, CD4+ leukocytes and ED-1+ macrophages infiltrated the ischemic organs in parallel with up-regulation of major histocompatibility complex class II antigen expression. Because macrophages have been shown to be critical in chronic changes in other models, they were examined primarily in these studies. By reverse transcriptase polymerase chain reaction, macrophage-derived, fibrosis-inducing factors (transforming growth factor-beta, interleukin 6, and tumor necrosis factor-alpha) remained highly and constantly expressed throughout the follow-up period. The long-term influence of initial treatment with the soluble form of P-selectin glycoprotein ligand-1, a soluble ligand for P- and E-selectin, was then examined. All functional and structural changes remained at relative baseline, similar to uninephrectomized controls.These data suggest that blocking the initial selectin-mediated step after ischemia/reperfusion injury, which triggers significant early cellular and molecular events, also reduces later renal dysfunction and tissue damage over time. In part, the findings may be explained by the sparing of functioning nephron units, which if destroyed or compromised by the original insult, may contribute to long-term graft failure. This approach may be important clinically in the transplantation of kidneys from non-heart-beating or marginal donors or organs experiencing prolonged ischemic times.

View details for Web of Science ID 000071034100003

View details for PubMedID 9415550
CD28-B7 blockade in organ dysfunction secondary to cold ischemia/reperfusion injury - Rapid Communication KIDNEY INTERNATIONAL Chandraker, A., Takada, M., Nadeau, K. C., Peach, R., Tilney, N. L., Sayegh, M. H. 1997; 52 (6): 1678-1684
Abstract

Ischemic injury to cadaver organs is a major risk factor for development of chronic organ dysfunction. We have recently shown that the B7 costimulatory pathway plays a critical role in early organ dysfunction developing after renal cold ischemia/reperfusion injury. We extended these observations to investigate the role of this pathway in the development and progression of chronic organ dysfunction following such injury. Uninephrectomized rats which underwent cold ischemia/reperfusion injury developed progressive proteinuria as compared to uninephrectomized controls. Animals treated with CTLA4Ig, which blocks B7 costimulation, starting on the day of injury had significantly better long-term survival and developed significantly less proteinuria than control animals treated with control Ig. RT-PCR analysis of kidney tissue showed significant reduction in expression of activation and inflammatory cytokines, chemoattractants, and growth factors, as compared to controls. Delaying administration of CTLA4Ig for one week, but not four weeks, after injury was still effective in ameliorating development of progressive proteinuria. Interestingly, selective blockade of B7-1 by a mutant form of CTLA4Ig had no effect on early or chronic organ dysfunction. These findings indicate the long-term functional and molecular consequences of experimental cold ischemia/reperfusion injury, and suggest that B7-2 is critical in the development of organ dysfunction following ischemic injury, even in the absence of alloantigen.

View details for Web of Science ID A1997YH57300028

View details for PubMedID 9407517
The role of the B7 costimulatory pathway in experimental cold ischemia/reperfusion injury JOURNAL OF CLINICAL INVESTIGATION Takada, M., Chandraker, A., Nadeau, K. C., Sayegh, M. H., Tilney, N. L. 1997; 100 (5): 1199-1203
Abstract

Ischemia/reperfusion injury associated with organ retrieval and storage influences the development of chronic graft dysfunction, the major clinical problem in solid organ transplantation. The potential role of mononuclear cells (T cells and monocyte/macrophages) in this type of injury is unknown. Inbred male Lewis rats were uninephrectomized and the left kidney perfused in situ with 10 ml of iced University of Wisconsin solution. Immunohistological studies showed mononuclear cell infiltration of the ischemic organs associated with the upregulation of MHC class II antigen expression. Reverse transcriptase-PCR indicated that T cell associated cytokines and monocyte/macrophage activation markers/products are upregulated early after the ischemic insult. B7 expression occurred within 24 h and peaked at 3 d. Plasma creatinine levels rose transiently with complete recovery of renal function by 5 d. Animals began to develop progressive proteinuria after 8-12 wk, indicative of the long-term functional consequences of early ischemia/reperfusion injury. Blockade of T cell CD28-B7 costimulation with CTLA4Ig resulted in significant inhibition of T cell and macrophage infiltration and activation in situ. Treated animals did not exhibit transient renal dysfunction, nor developed proteinuria over time. This is the first demonstration that blocking T cell costimulatory activation in the absence of alloantigen can prevent the early and late consequences of ischemia/reperfusion injury.

View details for Web of Science ID A1997XV75300029

View details for PubMedID 9276737
Cellular and molecular predictors of chronic renal dysfunction after initial ischemia/reperfusion injury of a single kidney TRANSPLANTATION Azuma, H., Nadeau, K., Takada, M., Mackenzie, H. S., Tilney, N. L. 1997; 64 (2): 190-197
Abstract

Initial ischemia/reperfusion injury occurring secondary to organ retrieval, storage, and transplantation has been associated with late renal allograft deterioration and failure. In addition, there is an apparent synergy, reported in several clinical series, between the initial injuries of ischemia/reperfusion and acute rejection; the long-term results of graft survival are significantly deceased after both events in combination as compared with either alone or if no such episodes occur.In the present study, we examined patterns of proteinuria, cellular infiltration, cytokine expression, and glomerulosclerosis over time in Lewis and Fischer 344 rats after 45 min of warm ischemia of a single kidney and with or without contralateral nephrectomy. Both early (4 hr to 7 days) and late (2-52 weeks) events were studied serially in the affected kidneys morphologically, by immunohistology and by reverse transcriptase polymerase chain reaction.Intercellular adhesion molecule 1, endothelin, and major histocompatibility complex class II expression were up-regulated within 2 to 5 days after injury; T cells and macrophages increased transiently. Proteinuria developed after approximately 8 weeks only in animals bearing a single injured kidney, and not in those with a retained native organ. Progressive morphological changes occurred after 16 weeks, including glomerulosclerosis, arterial obliteration, and interstitial fibrosis. After a period of relative quiescence, expression of intercellular adhesion molecule 1 again increased in relation to progressive macrophage infiltration and their associated products, particularly, interleukin 1, tumor necrosis factor-alpha, transforming growth factor-beta, and inducible nitric oxide synthase. Monocyte chemotactic protein 1 was intensely up-regulated by 24 weeks, coincident with a dramatic rise in this infiltrating population. These changes remained virtually at baseline in animals with a retained native kidney.These data imply that chronic injury after significant initial ischemia and reperfusion occurs when there is already a 50% renal mass reduction, but not when two kidneys remain in place. Permanent nephron loss resulting from such an insult could account for this phenomenon. Early ischemia and reperfusion, if severe enough in a single kidney, may be an important antigen-independent risk factor for later renal deterioration and failure. In the context of a renal allograft, it may contribute to chronic rejection.

View details for Web of Science ID A1997XN86900002

View details for PubMedID 9256172
The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney - Inhibition by a soluble P-selectin ligand JOURNAL OF CLINICAL INVESTIGATION Takada, M., Nadeau, K. C., SHAW, G. D., MARQUETTE, K. A., Tilney, N. L. 1997; 99 (11): 2682-2690
Abstract

Ischemia/reperfusion (I/R) injury associated with renal transplantation may influence both early graft function and late changes. The initial (
View details for Web of Science ID A1997XD35700018

View details for PubMedID 9169498
Sequential cellular and molecular kinetics in acutely rejecting renal allografts in rats TRANSPLANTATION Nagano, H., Nadeau, K. C., Takada, M., Kusaka, M., Tilney, N. L. 1997; 63 (8): 1101-1108
Abstract

The initial (0-24 hr), early (3-5 days), and late (7-14 days) events occurring in LBNF1 renal allografts transplanted into Lew recipients were examined to define precisely the sequential cellular and molecular kinetics during acute rejection. Grafts and spleens were harvested at 3, 6, 12, and 24 hr, and at 3, 5, 7, and 14 days and processed for morphology, immunohistology, and reverse transcriptase-polymerase chain reaction. Various factors (mRNA) were up-regulated sequentially in the allografts over time. In the initial phase, E-selectin and complement (C1 and C3) expression was noted within 6 hr, peaking by 24 hr. RANTES (regulated upon activation, normal T cell expressed and secreted) increased within 6 hr, and then again between 3 and 6 days. By immunohistology, MHC class II was up-regulated consistently after day 1. Intercellular adhesion molecule-1 expression increased after day 3; lymphocyte function-associated antigen-1+ infiltrating leukocytes peaked at day 5. Infiltrating CD8+ T lymphocytes increased strikingly between days 1 and 3, peaking at day 5; CD4+ cells infiltrated more slowly until day 5. The kinetics of ED1+ macrophages were similar to those of lymphocyte function-associated antigen-1+ cells. The CD4+ T cell-derived product, interleukin (IL)-2, peaked at 7 days. Interferon-gamma increased progressively up to 14 days. By 3 days, the macrophage-associated factor, transforming growth factor-beta, peaked; this was followed by increased IL-6 expression by day 5. IL-1, tumor necrosis factor-alpha, and inducible nitric oxide synthase increased slowly until day 7, declining thereafter. Endothelin increased progressively over the 14-day follow-up period. Cytokine dynamics occurring in host spleen were similar to those noted in the allografts. Although acute rejection is primarily T cell mediated, adhesion molecules, macrophages, and their associated products may influence initial and later changes. The brisk expression of complement, E-selectin, and RANTES within the first few hours after engraftment may occur secondary to ischemic injury and trigger subsequent immunological events. Macrophages and their products may play a larger role in the process than hitherto appreciated.

View details for Web of Science ID A1997WW66000009

View details for PubMedID 9133471
Unaccompanied children in detention in the US PEDIATRICS Nadeau, K. C. 1997; 99 (4): 653-653
View details for Web of Science ID A1997WQ80200052

View details for PubMedID 9093327
Immigrating unaccompanied miners - A neglected minority? WESTERN JOURNAL OF MEDICINE Nadeau, K., Hannibal, K., Sirkin, S., Nightingale, E. O. 1997; 166 (3): 221-221
View details for Web of Science ID A1997WW66700014

View details for PubMedID 9143205
Nephron mass modulates the hemodynamic, cellular, and molecular response of the rat renal allograft TRANSPLANTATION Azuma, H., Nadeau, K., Mackenzie, H. S., BRENNER, B. M., Tilney, N. L. 1997; 63 (4): 519-528
Abstract

Functioning nephron mass has recently been implicated as a risk factor for development of chronic "rejection" of kidney allografts. Reductions in nephron number below 50% may induce glomerular hypertension and hyperfiltration in surviving units, which in turn lead to graft injury. In the present study, which extends and amplifies our previous investigations, cellular and molecular characteristics of single allografts from F344 donors in bilaterally nephrectomized LEW recipients, our standard experimental model of chronic renal allograft dysfunction, were compared with allografts from recipients where total renal mass was reduced (by ligating branches of the graft renal artery) or restored to normal levels by transplanting or retaining a second kidney. Our findings in this study confirm that progressive proteinuria and structural injury in recipients of single allografts were accentuated in grafts with reduced mass but virtually absent in rats with increased kidney mass. A striking observation was that patterns of cell surface molecule expression, cellular infiltration, and expression of all T cell- and macrophage-associated products studied were all markedly modulated by changes in renal mass. Moreover, several molecules that are up-regulated before evidence of graft injury are down-regulated by providing increased renal mass. These data show that the quantity of functioning renal mass is not only an important independent determinant of the tempo and intensity of chronic renal allograft failure, but also a potent modulator of fundamental cellular and molecular components of a complex process. This phenomenon involves antigen-dependent and antigen-independent elements that ultimately result in chronic allograft failure.

View details for Web of Science ID A1997WL85500006

View details for PubMedID 9047144
Inhibition of CD28-B7 T-cell costimulatory activation pathway affects intragraft cytokine and growth factor expression in chronic renal allograft rejection XVI International Congress of the Transplantation-Society Nadeau, K., Azuma, H., Chandraker, A., Sayegh, M. H., Tilney, N. L. ELSEVIER SCIENCE INC. 1997: 1038?38
View details for Web of Science ID A1997WM12700453

View details for PubMedID 9123187
Initial ischemia/reperfusion injury influences late functional and structural changes in the kidney XVI International Congress of the Transplantation-Society Azuma, H., Nadeau, K., Takada, M., Tilney, N. L. ELSEVIER SCIENCE INC. 1997: 1528?29
View details for Web of Science ID A1997WM12700678

View details for PubMedID 9123412
Early cellular and molecular changes in ischemia/reperfusion injury: Inhibition by a selectin antagonist, P-selectin glycoprotein ligand-1 XVI International Congress of the Transplantation-Society Takada, M., Nadeau, K. C., SHAW, G. D., Tilney, N. L. ELSEVIER SCIENCE INC. 1997: 1324?25
View details for Web of Science ID A1997WM12700591

View details for PubMedID 9123325
Sequential cytokine expression in renal allografts in rats immunosuppressed with maintenance cyclosporine or mycophenolate mofetil TRANSPLANTATION Nadeau, K. C., Azuma, H., Tilney, N. L. 1996; 62 (9): 1363-1366
Abstract

Although the immunosuppressive agents used clinically modulate acute rejection of organ allografts, their ability to prevent chronic rejection has been less clear. To ascertain the effects of prolonged maintenance treatment with cyclosporine (CsA) and mycophenolate mofetil, we examined sequential patterns of cytokine regulation by reverse transcriptase polymerase chain reaction in long-surviving renal allografts in treated recipients. In renal allografts in animals on long-term CsA therapy, there is important up-regulation of transforming growth factor-beta, Hsp70, and endothelin as compared with control animals. Conversely, interleukin-2 receptor, interferon-gamma, and tumor necrosis factor-alpha in kidney grafts in this group were expressed at lower levels compared with those noted in chronically rejecting grafts in control animals that had received only CsA for 10 days after transplantation. Morphologically, the long-term CsA-treated kidneys had more extensive arterial obliterative changes and glomerulosclerosis after 24 weeks than control organs; these changes can presumably be attributed to the nephrotoxic effects of this drug combined with the progressive changes of chronic rejection. In contrast, mycophenolate mofetil inhibited the production of all lymphocyte and macrophage-derived cytokines throughout the entire follow-up period. Allograft kidneys in these latter recipients showed no late morphological abnormalities. This agent may be important clinically in preventing chronic rejection.

View details for Web of Science ID A1996VU11700034

View details for PubMedID 8932288
Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Azuma, H., Chandraker, A., Nadeau, K., Hancock, W. W., Carpenter, C. B., Tilney, N. L., Sayegh, M. H. 1996; 93 (22): 12439-12444
Abstract

Blocking CD28-B7 T-cell costimulation by systemic administration of CTLA4Ig, a fusion protein which binds B7 molecules on the surface of antigen-presenting cells, prevents rejection and induces tolerance in experimental acute allograft rejection models. We tested the effect of CTLA4Ig therapy on the process of chronic renal allograft rejection using an established experimental transplantation model. F344 kidneys were transplanted orthotopically into bilaterally nephrectomized LEW recipients. Control animals received low dose cyclosporine for 10 days posttransplantation. Administration of a single injection of CTLA4Ig on day 2 posttransplant alone or in addition to the low dose cyclosporine protocol resulted in improvement of long-term graft survival as compared with controls. More importantly, control recipients which received cyclosporine only developed progressive proteinuria by 8-12 weeks, and morphological evidence of chronic rejection by 16-24 weeks, including widespread transplant arteriosclerosis and focal and segmental glomerulosclerosis, while animals treated with CTLA4Ig alone or in addition to cyclosporine did not. Competitive reverse transcriptase-PCR and immunohistological analysis of allografts at 8, 16, and 24 weeks showed attenuation of lymphocyte and macrophage infiltration and activation in the CTLA4Ig-treated animals, as compared with cyclosporine-alone treated controls. These data confirm that early blockade of the CD28-B7 T-cell costimulatory pathway prevents later development and evolution of chronic renal allograft rejection. Our results indicate that T-cell recognition of alloantigen is a central event in initiating the process of chronic rejection, and that strategies targeted at blocking T-cell costimulation may prove to be a valuable clinical approach to preventing development of the process.

View details for Web of Science ID A1996VP93700071

View details for PubMedID 8901600
Inflammatory mediators, cells and their products in acute host alloresponsiveness. Annals of transplantation Tilney, N. L., Nadeau, K. 1996; 1 (3): 5-13
View details for PubMedID 9869913
Prevention of functional, structural, and molecular changes of chronic rejection of rat renal allografts by a specific macrophage inhibitor 14th Annual Meeting of the American-Society-of-Transplant-Physicians Azuma, H., Nadeau, K. C., Ishibashi, M., Tilney, N. L. WILLIAMS & WILKINS. 1995: 1577?82
Abstract

Chronic rejection is the primary cause of long-term allograft loss. Macrophages and their products have been shown to be critical in the development of this process in an established kidney allograft rat model. A new synthetic agent, Gamma lactone, is a specific inhibitor of macrophages and monocytes that inhibits the generation of these populations in vitro and their activities in the effector phase of host alloresponsiveness. We tested its effects on the development of chronic changes in the model. Untreated control allograft recipients developed increasing proteinuria after 12 weeks; progressive glomerulosclerosis, interstitial fibrosis, and arterial obliteration developed thereafter. Infiltrating ED1+ macrophages as noted by immunohistology increased dramatically between 12 and 16 weeks, localizing preferentially in glomeruli and perivascular areas. The presence of these cells was associated with dense expression of their products. Reverse transcription polymerase chain reaction confirmed and expanded the immunohistological findings, showing significant gene expression of macrophage-derived mediators. In contrast, recipients treated with G-Lac daily for 32 weeks never developed proteinuria; macrophage infiltration was dramatically reduced, and expression of their products was virtually absent. At 32 weeks, most glomeruli and arteries remained histologically normal. In another group in which treatment was stopped at 24 weeks, however, proteinuria began to develop by 32 weeks; macrophages infiltrated the organs and expression of their products became manifest. These results confirm the importance of macrophages and macrophage-derived factors in chronic rejection and suggest that a specific inhibitor of macrophage activation may be useful in the prevention of the process over the long term.

View details for Web of Science ID A1995TN23000034

View details for PubMedID 8545893
SEQUENTIAL CYTOKINE DYNAMICS IN CHRONIC REJECTION OF RAT RENAL-ALLOGRAFTS - ROLES FOR CYTOKINES RANTES AND MCP-1 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Nadeau, K. C., Azuma, H., Tilney, N. L. 1995; 92 (19): 8729-8733
Abstract

Chronic rejection, the most important cause of long-term graft failure, is thought to result from both alloantigen-dependent and -independent factors. To examine these influences, cytokine dynamics were assessed by semiquantitative competitive reverse transcriptase-PCR and by immunohistology in an established rat model of chronic rejection lf renal allografts. Isograft controls develop morphologic and immunohistologic changes that are similar to renal allograft changes, although quantitatively less intense and at a delayed speed; these are thought to occur secondary to antigen-independent events. Sequential cytokine expression was determined throughout the process. During an early reversible allograft rejection episode, both T-cell associated [interleukin (IL) 2, IL-2 receptor, IL-4, and interferon gamma] and macrophage (IL-1 alpha, tumor necrosis factor alpha, and IL-6) products were up-regulated despite transient immunosuppression. RANTES (regulated upon activation, normal T-cell expressed and secreted) peaked at 2 weeks; intercellular adhesion molecule (ICAM-1) was maximally expressed at 6 weeks. Macrophage products such as monocyte chemoattractant protein (MCP-1) increased dramatically (to 10 times), presaging intense peak macrophage infiltration at 16 weeks. In contrast, in isografts, ICAM-1 peaked at 24 weeks. MCP-1 was maximally expressed at 52 weeks, commensurate with a progressive increase in infiltrating macrophages. Cytokine expression in the spleen of allograft and isograft recipients was insignificant. We conclude that chronic rejection of kidney allografts in rats is predominantly a local macrophage-dependent event with intense up-regulation of macrophage products such as MCP-1, IL-6, and inducible nitric oxide synthase. The cytokine expression in isografts emphasizes the contribution of antigen-independent events. The dynamics of RANTES expression between early and late phases of chronic rejection suggest a key role in mediating the events of the chronic process.

View details for Web of Science ID A1995RU75900040

View details for PubMedID 7568006
QUANTITATION OF THE INTERACTION OF THE IMMUNOSUPPRESSANT DEOXYSPERGUALIN AND ANALOGS WITH HSC70 AND HSP90 BIOCHEMISTRY Nadeau, K., Nadler, S. G., Saulnier, M., Tepper, M. A., Walsh, C. T. 1994; 33 (9): 2561-2567
Abstract

Deoxyspergualin (DSG), a spermidinyl, alpha-hydroxyglycyl, 7-guanidinoheptanoyl peptidomimetic, shows immunosuppressive activity. In confirmation of a recent report that immobilized methoxyDSG selectively retains the heat shock protein Hsc70, we report here quantitative binding of DSG and analogs to both Hsc70 and the 90-kDa heat shock protein Hsp90. We have utilized affinity capillary electrophoresis to obtain Kd values for DSG and analogs, and stimulation of the ATPase activity of Hsc70 to obtain Km values for DSG, that are comparable and corroborative. Kd values are 4 microM for DSG binding to Hsc70 and 5 microM for DSG binding to Hsp90. Two active analogs, methoxy- and glycylDSG, bind with similar affinities. Glyoxylylspermidine and des(aminopropyl)DSG, two inactive metabolites, have much reduced affinity for Hsc70 and Hsp90. These data validate binding of these novel immunosuppressant agents to these molecular chaperones, at concentrations in the range of pharmacologically active doses, and indicate that further characterization of Hsc70 and/or Hsp90 as potential targets for DSG is warranted.

View details for Web of Science ID A1994MZ69700027

View details for PubMedID 8117717
MOLECULAR AND BIOCHEMICAL-COMPARISON OF THE 70-KDA HEAT-SHOCK PROTEINS OF TRYPANOSOMA-CRUZI JOURNAL OF BIOLOGICAL CHEMISTRY Olson, C. L., Nadeau, K. C., Sullivan, M. A., Winquist, A. G., Donelson, J. E., Walsh, C. T., Engman, D. M. 1994; 269 (5): 3868-3874
Abstract

An analysis of the genetic organization, regulated expression and biochemical properties of the cytoplasmic/nuclear (hsp70) and mitochondrial (mtp70) 70-kDa heat shock proteins of Trypanosoma cruzi is presented. The two proteins are encoded by tandemly arranged gene families that are located on different chromosomes. Both are mildly heat-inducible but have different optimal temperatures for expression. During the switch from proliferation to differentiation that occurs during the growth of T. cruzi in culture, the hsp70 level decreases dramatically while the mtp70 level falls only slightly. The subcellular locations of the two proteins differ during heat shock. While mtp70 remains associated with the kinetoplast at all temperatures, hsp70 becomes more concentrated in the nucleus at higher temperatures. Biochemical analysis of hsp70 and mtp70 revealed both to be potent ATPases. Each protein binds ATP with a Km of about 70 microM and hydrolyzes ATP with a kcat of about 100 min-1, 100 times greater than the kcat of human hsp70. The high ATPase activities of hsp70 and mtp70 are further stimulated by incubation with peptides, suggesting that these trypanosome heat shock proteins have protein chaperone activity. Finally, mtp70, but not hsp70, was found to possess autophosphorylation activity in vitro, a property that it shares with prokaryotic hsp70. These findings demonstrate unique cellular and biochemical characteristics of T. cruzi mtp70 and hsp70 that suggest that they play distinct physiologic roles in the biology of the cell.

View details for Web of Science ID A1994MV63100107

View details for PubMedID 8106432
HSP90 CHAPERONINS POSSESS ATPASE ACTIVITY AND BIND HEAT-SHOCK TRANSCRIPTION FACTORS AND PEPTIDYL PROLYL ISOMERASES JOURNAL OF BIOLOGICAL CHEMISTRY Nadeau, K., Das, A., Walsh, C. T. 1993; 268 (2): 1479-1487
Abstract

Heat shock proteins of the 82-90 kDa class (hsp82 and hsp90) are abundant, conserved, and ubiquitous from prokaryotes to eukaryotes. Although proposed to be chaperones, they had not been reported to possess enzymatic activity until our recent observation that pure trypanosomatid hsp83 had potent ATPase activity (Nadeau, K., Sullivan, M., Engman, D., and Walsh, C. T. (1992) Protein Sci. 1, 970-979). We have now purified the hsp90 homolog from Escherichia coli (HtpG) and from Saccharomyces cerevisiae (hsp82) to homogeneity and observe ATPase activity with kcat values of 3 min-1 and 140 min-1. In addition, examinations of purified rat hsp90 and human hsp90 detect ATPase activity with a kcat of 0.6 min-1 and 10 min-1. Each of these hsp90s undergoes autophosphorylation on serine or threonine residues. In prokaryotes and eukaryotes, the induction of hsps during heat shock is controlled, respectively, by the binding of an alternate sigma 32 or a transcriptional activator (heat shock factor or HSF) at heat shock promoter elements. Here we show that E. coli HtpG immobilized to Affi-Gel beads selectively retains sigma 32 while the yeast hsp90 and rat hsp90 retain HSF. The peptidyl prolyl isomerase hsp59 of the FK506 binding class is known to bind to hsp90. We also detect binding of the other family of PPIases, the cyclophilins, to immobilized hsp90, consistent with a functional convergence of protein foldases.

View details for Web of Science ID A1993KG07700106

View details for PubMedID 8419347
STUDIES ON THE INTERACTION OF THE IMMUNOSUPPRESSANT 15-DEOXYSPERGUALIN WITH HEAT-SHOCK PROTEINS Conference on Immunosuppressive and Antiinflammatory Drugs Nadler, S. G., Cleaveland, J., Tepper, M. A., Walsh, C., Nadeau, K. NEW YORK ACAD SCIENCES. 1993: 412?414
View details for Web of Science ID A1993BZ60M00047

View details for PubMedID 8109853
83-KILODALTON HEAT-SHOCK PROTEINS OF TRYPANOSOMES ARE POTENT PEPTIDE-STIMULATED ATPASES PROTEIN SCIENCE Nadeau, K., Sullivan, M. A., Bradley, M., Engman, D. M., Walsh, C. T. 1992; 1 (8): 970-979
Abstract

A Crithidia fasciculata 83-kDa protein purified during a separate study of C. fasciculata trypanothione synthetase was shown to have ATPase activity and to belong to the hsp90 family of stress proteins. Because no ATPase activity has previously been reported for the hsp90 class, ATP utilization by C. fasciculata hsp83 was characterized: this hsp83 has an ATPase kcat of 150 min-1 and a Km of 60 microM, whereas the homologous mammalian hsp90 binds ATP but has no ATPase activity. Crithidia fasciculata hsp83 undergoes autophosphorylation on serine and threonine at a rate constant of 3.3 x 10(-3) min-1. Similar analysis was performed on recombinant Trypanosoma cruzi hsp83, and comparable ATPase parameters were obtained (kcat = 100 min-1, Km = 80 microM, kautophosphorylation = 6.3 x 10(-3) min-1). The phosphoenzyme is neither on the ATPase hydrolytic pathway nor does it affect ATPase catalytic efficiency. Both C. fasciculata and T. cruzi hsp83 show up to fivefold stimulation of ATPase activity by peptides of 6-24 amino acids.

View details for Web of Science ID A1992JM67800002

View details for PubMedID 1304385
KINETIC ISOTOPE EFFECT ANALYSIS OF THE REACTION CATALYZED BY TRYPANOSOMA-CONGOLENSE TRYPANOTHIONE REDUCTASE BIOCHEMISTRY LEICHUS, B. N., Bradley, M., Nadeau, K., Walsh, C. T., Blanchard, J. S. 1992; 31 (28): 6414-6420
Abstract

African trypanosomes are devoid of glutathione reductase activity, and instead contain a unique flavoprotein variant, trypanothione reductase, which acts on a cyclic derivative of glutathione, trypanothione. The high degree of sequence similarity between trypanothione reductase and glutathione reductase, as well as the obvious similarity in the reactions catalyzed, led us to investigate the pH dependence of the kinetic parameters, and the isotopic behavior of trypanothione reductase. The pH dependence of the kinetic parameters V, V/K for NADH, and V/K for oxidized trypanothione has been determined for trypanothione reductase from Trypanosoma congolense. Both V/K for NADH and the maximum velocity decrease as single groups exhibiting pK values of 8.87 +/- 0.09 and 9.45 +/- 0.07, respectively, are deprotonated. V/K for oxidized trypanothione, T(S)2, decreases as two groups exhibiting experimentally indistinguishable pK values of 8.74 +/- 0.03 are deprotonated. Variable magnitudes of the primary deuterium kinetic isotope effects on pyridine nucleotide oxidation are observed on V and V/K when different pyridine nucleotide substrates are used, and the magnitude of DV and D(V/K) is independent of the oxidized trypanothione concentration at pH 7.25. Solvent kinetic isotope effects, obtained with 2',3'-cNADPH as the variable substrate, were observed on V only, and plots of V versus mole fraction of D2O (i.e., proton inventory) were linear, and yielded values of 1.3-1.6 for D2OV. Solvent kinetic isotope effects obtained with alternate pyridine nucleotides as substrates were also observed on V, and the magnitude of D2OV decreases for each pyridine nucleotide as its maximal velocity relative to that of NADPH oxidation decreases.(ABSTRACT TRUNCATED AT 250 WORDS)

View details for Web of Science ID A1992JE53600008

View details for PubMedID 1633154
PURIFICATION OF GLUTATHIONYLSPERMIDINE AND TRYPANOTHIONE SYNTHETASES FROM CRITHIDIA-FASCICULATA PROTEIN SCIENCE Smith, K., Nadeau, K., Bradley, M., Walsh, C., Fairlamb, A. H. 1992; 1 (7): 874-883
Abstract

Two enzymes involved in the biosynthesis of the trypanosomatid-specific dithiol trypanothione-glutathionylspermidine (Gsp) synthetase and trypanothione (TSH) synthetase--have been identified and purified individually from Crithidia fasciculata. The Gsp synthetase has been purified 93-fold and the TSH synthetase 52-fold to apparent homogeneity from a single DEAE fraction that contained both activities. This constitutes the first indication that the enzymatic conversion of two glutathione molecules and one spermidine to the N1,N8-bis(glutathionyl)spermidine (TSH) occurs in two discrete enzymatic steps. Gsp synthetase, which has a kcat of 600/min, shows no detectable TSH synthetase activity, whereas TSH synthetase does not make any detectable Gsp and has a kcat of 75/min. The 90-kDa Gsp synthetase and 82-kDa TSH synthetase are separable on phenyl Superose and remain separated on gel filtration columns in high salt (0.8 M NaCl). Active complexes can be formed under low to moderate salt conditions (0.0-0.15 M NaCl), consistent with a functional complex in vivo.

View details for Web of Science ID A1992JF88300005

View details for PubMedID 1304372
MOLECULAR STUDIES ON TRYPANOTHIONE REDUCTASE - AN ANTIPARASITIC TARGET ENZYME CURRENT TOPICS IN CELLULAR REGULATION Walsh, C., Bradley, M., Nadeau, K. 1992; 33: 409-417
View details for Web of Science ID A1992MD69600023

View details for PubMedID 1354149
MOLECULAR STUDIES ON TRYPANOTHIONE REDUCTASE, A TARGET FOR ANTIPARASITIC DRUGS TRENDS IN BIOCHEMICAL SCIENCES Walsh, C., Bradley, M., Nadeau, K. 1991; 16 (8): 305-309
Abstract

Trypanosoma and Leishmania are parasitic protozoa that cause a variety of diseases, which include African sleeping sickness and oriental sore. Attempts to determine pharmaceutically exploitable differences between host and parasite biochemistry have identified the unique trypanothione pathway as a possible target. This pathway includes the enzyme trypanothione reductase, the parasite analogue of glutathione reductase.

View details for Web of Science ID A1991GA13000013

View details for PubMedID 1957352
A TEST FOR GENETIC EXCHANGE IN MIXED INFECTIONS OF LEISHMANIA-MAJOR IN THE SAND FLY PHLEBOTOMUS-PAPATASI JOURNAL OF PROTOZOOLOGY PANTON, L. J., Tesh, R. B., Nadeau, K. C., Beverley, S. M. 1991; 38 (3): 224-228
Abstract

We tested if genetic exchange was observable between two strains of Leishmania major (Trypanosomatidae) during mixed infection of the sand fly Phlebotomus papatasi. Previous studies suggested that genetic exchange may occur in natural populations of Leishmania at a low frequency, but experimental crosses examining small numbers of progeny (less than 60) did not reveal hybrid parasites. Accordingly, a strategy was devised to increase the number of progeny that could be screened by 100-fold. Clonal derivatives from two strains that were infective to flies and contained numerous restriction fragment length polymorphisms were characterized and selected for resistance to methotrexate or tunicamycin by gene amplification. A successfully mixed infection of P. papatasi was obtained, and a method was developed for directly plating promastigotes from the gut contents of infected flies onto selective media. Twenty-five hundred independent progeny were scored for the presence of both drug resistance markers. No hybrid parasites were observed, indicating that the frequency of genetic exchange in this cross must be less than 4 x 10(-4). The lines and methods established in this work may prove useful in future studies of the mechanism and frequency of gene exchange in Leishmania.

View details for Web of Science ID A1991FQ06400010

View details for PubMedID 1880760
THE PROMOTER OF THE LATENCY-ASSOCIATED TRANSCRIPTS OF HERPES-SIMPLEX VIRUS TYPE-1 CONTAINS A FUNCTIONAL CAMP-RESPONSE ELEMENT - ROLE OF THE LATENCY-ASSOCIATED TRANSCRIPTS AND CAMP IN REACTIVATION OF VIRAL LATENCY PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Leib, D. A., Nadeau, K. C., Rundle, S. A., Schaffer, P. A. 1991; 88 (1): 48-52
Abstract

A 203-base-pair sequence 5' of the latency-associated transcripts (LATs) of herpes simplex virus type 1 contains a 7-base consensus sequence TGCGTCA that is identical to the cAMP-response element of the proenkephalin gene. This consensus sequence is at -38 relative to the putative 5' end of the LATs with a TATA box at the -24 position. In transient chloramphenicol acetyltransferase assays in rat pheochromocytoma (PC12) cells, this enhancer region stimulated gene expression up to 3-fold in the presence of dibutyryl cAMP, forskolin, nerve growth factor, or phorbol 12-myristate 13-acetate. Mutation of the cAMP-response element to TGCG-CAA resulted in a 4-fold reduction of basal activity and a complete loss of inducible stimulation. In DNA gel retardation assays, purified cAMP-response element-binding protein and a nuclear protein from PC12 cells were shown to bind specifically to this element. Furthermore, it was demonstrated that the reactivation of wild-type herpes simplex virus type 1 from dissociated latently infected murine trigeminal ganglia was significantly accelerated (P less than 0.005) by the addition of cAMP analogs or adenylate cyclase activators. However, these reagents did not accelerate reactivation of a deletion mutant that lacks the putative cAMP-response element-containing promoter region, transcriptional start site, and 1015 base pairs of the LATs. These studies demonstrate that the promoter region of the LATs contains a functional cAMP-response element and that expression of the LATs is likely controlled by second messenger signal transduction and imply a role for cAMP in triggering viral reactivation.

View details for Web of Science ID A1991EQ54400011

View details for PubMedID 1846042

Kari Nadeau, MD, PhD

Naddisy Foundation Professor of Pediatric Food Allergy, Immunology and Asthma, Professor of Pediatrics, Senior Fellow at the Woods Institute and Professor, by courtesy, of Otolaryngology and of Epidemiology and Population Health at LPCH

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