Publications

Stephen J. Galli, MD
Mary Hewitt Loveless, MD, Professor in the School of Medicine and Professor of Pathology and of Microbiology and Immunology

Publications

  • A phase 2 randomized controlled trial using biologics to improve multi OIT outcomes (COMBINE): design, rationale, and methods. Frontiers in allergy Long, A. J., Sindher, S., Martinez, K., Choi, J. H., Albarran, M., Schuetz, J., Parry, A., Tang, J., Garcia Llorett, M., Zedeck, S. S., Grissinger, A., Kiernan, E., Leonard, S., Raeber, O., Feight, C., Anderson, B., Sharma, R., Bogetic, D., Chin, A. R., Woch, M., Poyser, J., Laurienzo Panza, J., Togias, A., Wheatley, L., Boyd, S., Galli, S. J., Nadeau, K. C., Chinthrajah, R. S. 2025; 6: 1729111

    Abstract

    Food allergy remains a serious public health concern associated with significantly lowered quality of life and the risk of potentially life-threatening allergic reactions. While oral immunotherapy (OIT) has consistently demonstrated efficacy in the desensitization of multi-food allergic patients, many patients undergoing such treatment are burdened by dose-related side effects that can hinder their compliance and the overall efficacy of OIT. Recent efforts to improve upon OIT have begun to evaluate the concomitant use of biologics such as omalizumab and dupilumab with OIT for their ability to selectively inhibit pathways involved in the underlying pathology of food allergy.Herein, we detail the clinical trial design, rationale, and methods for a Phase 2 randomized, double-blind, placebo-controlled, multi-center study evaluating the safety and efficacy of omalizumab and/or dupilumab therapy in combination with participant-specific multi-food (mOIT) in patients aged 4-55 years, with multi-food allergy that includes peanut. In this two-arm superiority trial, participants will be randomized (5:5:1) to (1) omalizumab/placebo-dupilumab with mOIT (n = 50), (2) omalizumab/dupilumab with mOIT (n = 50), or (3) a mechanistic-only arm of placebo-omalizumab/dupilumab with mOIT (n = 10). Double-blind placebo-controlled food challenges (DBPCFCs) will be used to assess desensitization to ≥1,043 mg cumulative protein at Week 32, after which all treatment is to be discontinued. A follow-up assessment of sustained unresponsiveness via DBPCFCs will be conducted at Week 44.This trial tests the hypothesis that adding dupilumab to omalizumab-facilitated mOIT will increase the likelihood of inducing sustained unresponsiveness and decrease mOIT-related adverse events.

    View details for DOI 10.3389/falgy.2025.1729111

    View details for PubMedID 41488220

    View details for PubMedCentralID PMC12756116

  • Peanut allergy oral immunotherapy drives single-cell multi-omic changes in peanut-reactive T cells associated with sustained unresponsiveness. Nature immunology Han, X., Skatova, V., Mikelov, A., Ji, X., Hoh, R. A., Lee, J. Y., Cao, S., Seastedt, H., Schuetz, J., Fernandes, A., Singhal, A., Grubert, F., DeKruyff, R. H., Maecker, H. T., Galli, S. J., Manohar, M., Chinthrajah, R. S., Kasowski, M. M., Boyd, S. D., Nadeau, K. C. 2025

    Abstract

    Oral immunotherapy (OIT) is the only U.S. Food and Drud Administration-approved treatment for peanut allergy. Peanut-reactive (pr) CD4+ T cells are pivotal in peanut allergy pathogenesis and OIT-induced desensitization. However, the underlying pr CD4+ T cell immune mechanisms leading to sustained unresponsiveness after OIT discontinuation are largely unknown. We analyzed single-cell RNA and protein immunophenotypes and T cell receptor repertoires of pr CD4+ T cells from a phase 2 peanut OIT trial cohort. We identified increased cytotoxicity-related phenotypes and type 1 helper cytotoxic T lymphocyte-like cell clonal expansion during OIT, while type 2 helper T (TH2) cell-related phenotypes and TH2-like cell clonal expansion decreased. OIT participants achieving sustained unresponsiveness were distinguished by lower baseline TH2-related phenotypes, elevated post-OIT cytotoxicity-related pr effector T cell gene signatures and higher CD39 expression in pr regulatory T cells. These findings clarify OIT-induced CD4+ T cell tolerance mechanisms and can guide effective allergen-specific OIT strategies.

    View details for DOI 10.1038/s41590-025-02323-3

    View details for PubMedID 41188408

    View details for PubMedCentralID 7223701

  • Mouse and human mast cells can release pre-stored CSF1. The Journal of allergy and clinical immunology Galli, S. J. 2025

    View details for DOI 10.1016/j.jaci.2025.09.001

    View details for PubMedID 40962070

  • Discovery and Mechanistic Insights into Vascular Permeability Factor/Vascular Endothelial Growth Factor through the Work of Harold F. Dvorak and Ann M. Dvorak. The American journal of pathology Galli, S. J. 2025; 195 (8): 1360-1362

    View details for DOI 10.1016/j.ajpath.2024.08.017

    View details for PubMedID 40713220

  • Evolution of Mast Cell Research Associated with the Laboratory of Allergic Diseases: 1985-2022 Presented at 2023 NIAID Symposium. The Journal of allergy and clinical immunology Komarow, H. D., Nilsson, G., Okayama, Y., Mekori, Y. A., Olivera, A., Valent, P., Hartmann, K., Brockow, K., Cruse, G., Lyons, J. J., Klion, A. D., Akin, C., Gotlib, J., Castells, M., Galli, S. J., Metcalfe, D. D., Carter, M. C. 2025

    Abstract

    Present and former investigators of the Mast Cell Biology Section (MCBS) of the Laboratory of Allergic Diseases (LAD) and their colleagues organized a day long symposium in October of 2023 to honor the outstanding contributions of the MCBS headed by Dr. Dean D. Metcalfe, who recently retired from his leadership role in this department. The symposium featured an overview of discoveries that advanced the scientific understanding of the human mast cell lineage and compartment over the preceding three decades. Insights into mechanisms and molecules contributing to mast cell expansion and function in health and disease, mast cell activation, and neoplastic mast cells in mastocytosis were presented. The impact of these discoveries on the diagnosis and management of allergic diseases and mast cell disorders, as well as unmet needs in mast cell research, were reviewed. A summary of these discussions is presented in the current article.

    View details for DOI 10.1016/j.jaci.2025.06.029

    View details for PubMedID 40633596

  • A hand-operated microfluidic sample preparation-to-analysis workflow for simplifying the basophil activation test. Lab on a chip Castano, N., Chua, K., Nguyen, A., Marshall, W., Hofmann, G. H., Lee, J., Tsai, M., Sindher, S. B., Nadeau, K. C., Chinthrajah, R. S., Galli, S. J., Tang, S. K. 2025

    Abstract

    Access to the basophil activation test (BAT) has been hindered by the requirement for fresh blood analysis, specialized laboratory equipment, and advanced technical expertise. To address these issues, we have developed a hand-operated microfluidic sample preparation "muF-prep" device to perform the most time sensitive steps of the assay and stabilize the sample, effectively extending the time window before flow cytometry analysis. The muF-prep device performs concurrent basophil stimulation and staining for eight conditions in parallel. Barcoded staining of basophils allows the pooling of all conditions into one lyse/fix buffer tube for sample stabilization. After flow cytometry analysis, an XGBoost-enabled analysis pipeline unpools the eight conditions and generates basophil counts and activation levels directly from raw flow cytometry data. To characterize the muF-prep device, we stimulate whole blood samples from peanut-allergic and non-allergic donors. We compare muF-prep with a conventional BAT sample preparation protocol ("conv-prep"), and assess the stability of stimulated samples stored in the lyse/fix buffer. The muF-prep device performs sample preparation with <2 minutes of active user engagement. Our analysis pipeline shows excellent agreement with manual gating analysis. Compared with conv-prep, muF-prep exhibits similar activation levels at peanut doses of 1-100 ng mL-1, maximum activation levels, area under the dose response curve, and EC50 values. Activation levels of basophils from anonymous and presumed non-allergic donors in samples stored in the lyse/fix buffer for up to 7 days at 4 °C are similar to those analyzed on day 0. In summary, we demonstrate the potential of muF-prep to facilitate access to the BAT by simplifying sample preparation, stabilizing samples to remove the need for overnight blood shipping for flow cytometry analysis, and automating the data analysis pipeline.

    View details for DOI 10.1039/d5lc00037h

    View details for PubMedID 40600291

  • Evaluation of a method to simplify sample preparation for basophil activation tests Castano, N., Nguyen, A., Cai, N., Lee, J., Marshall, W., Chua, K., Hofmann, G., Somen, D., Cao, S., Tsai, M., Desai, M., Sindher, S., Chinthrajah, R., Galli, S., Nadeau, K., Tang, S. MOSBY-ELSEVIER. 2025: AB45

    View details for Web of Science ID 001466121700140

  • Baseline Epitope-Specific IgE Profiles are Predictive of Sustained Unresponsiveness or High Threshold One-Year Post OIT in the POISED Trial. The Journal of allergy and clinical immunology Suprun, M., Eun Lee, A. S., Getts, R., Peck, S., Sindher, S. B., Nadeau, K. C., Chinthrajah, R. S., Galli, S. J., Sampson, H. 2024

    Abstract

    BACKGROUND: Results from the POISED trial suggest that discontinuation of peanut oral immunotherapy can increase the risk of regaining clinical reactivity to peanut.OBJECTIVE: We sought to determine whether those who achieved sustained unresponsiveness (SU) or sustained high threshold (SHT) have different baseline sequential epitope-specific (es-) IgE profiles than those who achieved transient desensitization (TD).METHODS: Subjects in the POISED trial (NCT02103270) were randomized to peanut (n=95) or placebo (n=25) for 24 months. OIT-desensitized subjects were then assigned to no peanut (PN-0, n=51) or 300mg (PN-300, n=30) for 12 months. SU and SHT were determined by those in PN-0 and PN-300, respectively, passing 4000mg peanut oral challenge. Specific IgE and IgG4 levels to peanut, Ara h 1-3 proteins and 64 allergenic epitopes were measured. We developed machine learning glmnet models with bootstrap simulations using baseline data to predict SU/SHT.RESULTS: Eighty (84%) subjects were desensitized to peanut. Of those, 13% (n=8) and 37% (n=13) achieved SU/SHT in PN-0 and PN-300. Decreases in epitope-and protein-specific IgE levels and increases in IgG4 levels were observed during 2 years of OIT. At baseline, patients with SU in Peanut-0 but not Peanut-300 had lower es-IgE and protein-sIgE levels compared to the TD group. A machine-learning model with 12 baseline es-IgEs and age could predict SU/SHT with an accuracy of 94%, AUC 0.97, Sensitivity 1.00, Specificity 0.91.CONCLUSIONS: Patients who achieved SU/SHT have different baseline protein-and epitope-specific IgE profiles than those with TD. These profiles may help identify patients with an increased likelihood of achieving SU/SHT.

    View details for DOI 10.1016/j.jaci.2024.10.017

    View details for PubMedID 39505279

  • Role of allergen immunotherapy and biologics in allergic diseases. Current opinion in immunology Zhou, X., Simonin, E. M., Jung, Y. S., Galli, S. J., Nadeau, K. C. 2024; 91: 102494

    Abstract

    The rise in the prevalence of allergic diseases has become a global health burden. Allergic diseases are a group of immune-mediated disorders characterized by IgE-mediated conditions resulting from a type 2 helper T cell (Th2)-skewed immune response. This review aims to comprehensively summarize recent research on the roles of allergen immunotherapy (AIT) and biologics in allergic diseases. Specifically, we review the mechanisms of AIT and biologics in modulating innate and adaptive immunity involved in allergic disease pathogenesis, as well as their safety and efficacy in the treatment of allergic diseases. We also discuss current new AIT strategies such as recombinant allergen-based vaccines and allergen extract nanoencapsulation. Further research is needed to understand immune tolerance mechanisms beyond the Th2 pathway and to characterize immunological changes in responders and nonresponders to AIT or biologics. This additional research may uncover new targets for monitoring treatment responses and developing personalized treatment strategies for allergic diseases.

    View details for DOI 10.1016/j.coi.2024.102494

    View details for PubMedID 39357079

  • Association of cytotoxic effector memory CD8+ T cells with sustained unresponsiveness after peanut oral immunotherapy. Allergy Seastedt, H., Han, X., Fernandes, A., Galli, S. J., Boyd, S. D., Nadeau, K. C., Manohar, M., Chinthrajah, S. 2024

    View details for DOI 10.1111/all.16307

    View details for PubMedID 39244697