Melissa Mavers

All Publications

• Activation of the DR3-TL1A Axis in Donor Mice Leads to Regulatory T Cell Expansion and Activation With Reduction in Graft-Versus-Host Disease. Frontiers in immunology Mavers, M., Simonetta, F., Nishikii, H., Ribado, J. V., Maas-Bauer, K., Alvarez, M., Hirai, T., Turkoz, M., Baker, J., Negrin, R. S. 2019; 10: 1624

  Abstract

  Death receptor 3 (DR3) is a tumor necrosis factor receptor superfamily member (TNFRSF25), which is minimally expressed on resting conventional T cells (though readily inducible upon cell activation), yet highly expressed on resting FoxP3+ regulatory T cells (Treg). We recently demonstrated that activation of DR3 with an agonistic antibody (4C12) leads to selective expansion and activation of Treg in healthy mice and suppression of graft-versus-host disease (GVHD) in recipient mice when donor mice are treated. However, given the long antibody half-life and concomitant safety concerns, along with the lack of a humanized agonistic antibody to DR3, both human and murine fusion proteins incorporating the natural DR3 ligand TL1A (TL1A-Ig) have been developed. Herein, we show that DR3 activation with 4C12 or with TL1A-Ig, with or without the addition of low dose IL-2 to the treatment regimen, led to a significant expansion of murine Treg in spleen, lymph nodes, and peripheral blood. Bioluminescent imaging revealed peak Treg expansion around day 7-8, with return to near baseline after 2-3 weeks. In addition to expansion, all DR3 agonist treatment regimens led to increased activation of Tregs, with significant upregulation of the activation markers ICOS, KLRG-1, PD-1, and CD103, and the proliferation marker Ki-67. The near absence of activated Treg populations in control treated spleens was also detected on tSNE analysis of flow cytometry data. Subtly different patterns of splenic Treg activation by the different DR3 agonists were noted in both tSNE analysis of flow cytometry data and RNA-sequencing analysis. However, upregulation of gene transcripts which play important roles in cell proliferation, trafficking, activation, and effector function were observed regardless of the DR3 agonist treatment regimen used. In the major MHC-mismatch model of hematopoietic cell transplantation, DR3 agonist-mediated expansion and activation of Tregs in donor mice led to a significant improvement in GVHD in recipient mice. These data provide important preclinical information regarding the outcome of DR3 activation with an agonistic antibody or natural ligand and provide insight into the therapeutic use of this approach to reduce GVHD in recipients and improve outcomes of hematopoietic cell transplantation.

  View details for DOI 10.3389/fimmu.2019.01624

  View details for PubMedID 31379829

  View details for PubMedCentralID PMC6652149

• Invariant Natural Killer T Cell Subsets Have Diverse Functions: iNKT2 and iNKT17 Protect from Graft-Versus-Host-Disease, Whereas iNKT1 Have Antitumor Potential Maas-Bauer, K., Simonetta, F., Hirai, T., Wenokur, A., Fazal, F., Kambham, N., Ribado, J., Mavers, M., Baker, J., Bhatt, A. S., Chang, H. Y., Negrin, R. S. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113673

  View details for Web of Science ID 000454837601184

• High-Risk Leukemia: Past, Present, and Future Role of NK Cells JOURNAL OF IMMUNOLOGY RESEARCH Mavers, M., Bertaina, A. 2018: 1586905

  Abstract

  Natural killer (NK) cells are a population of cytotoxic innate lymphocytes that evolved prior to their adaptive counterparts and constitute one of the first lines of defense against infected/mutated cells. Several studies have shown that in patients with acute leukemia given haploidentical hematopoietic stem cell transplantation, donor-derived NK cells play a key role in the eradication of cancer cells. The antileukemic effect is mostly related to the presence of "alloreactive" NK cells, that is, mature KIR+ NK cells that express inhibitory KIR mismatched with HLA class I (KIR-L) of the patient. A genotypic analysis detecting KIR B haplotype and the relative B content is an additional donor selection criterion. These data provided the rationale for implementing phase I/II clinical trials of adoptive infusion of either selected or ex vivo-activated NK cells, often from an HLA-mismatched donor. In this review, we provide a historical perspective on the role played by NK cells in patients with acute leukemia, focusing also on the various approaches to adoptive NK cell therapy and the unresolved issues therein. In addition, we outline new methods to enhance NK activity, including anti-KIR monoclonal antibody, bi-/trispecific antibodies linking NK cells to cytokines and/or target antigens, and CAR-engineered NK cells.

  View details for PubMedID 29850617

  View details for PubMedCentralID PMC5925205

• Invariant Natural Killer T Cells As Suppressors of Graft-versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation. Frontiers in immunology Mavers, M., Maas-Bauer, K., Negrin, R. S. 2017; 8: 900

  Abstract

  Invariant natural killer T (iNKT) cells serve as a bridge between innate and adaptive immunity and have been shown to play an important role in immune regulation, defense against pathogens, and cancer immunity. Recent data also suggest that this compartment of the immune system plays a significant role in reducing graft-versus-host disease (GVHD) in the setting of allogeneic hematopoietic stem cell transplantation. Murine studies have shown that boosting iNKT numbers through certain conditioning regimens or adoptive transfer leads to suppression of acute or chronic GVHD. Preclinical work reveals that iNKT cells exert their suppressive function by expanding regulatory T cells in vivo, though the exact mechanism by which this occurs has yet to be fully elucidated. Human studies have demonstrated that a higher number of iNKT cells in the graft or in the peripheral blood of the recipient post-transplantation are associated with a reduction in GVHD risk, importantly without a loss of graft-versus-tumor effect. In two separate analyses of many immune cell subsets in allogeneic grafts, iNKT cell dose was the only parameter associated with a significant improvement in GVHD or in GVHD-free progression-free survival. Failure to reconstitute iNKT cells following allogeneic transplantation has also been associated with an increased risk of relapse. These data demonstrate that iNKT cells hold promise for future clinical application in the prevention of GVHD in allogeneic stem cell transplantation and warrant further study of the immunoregulatory functions of iNKT cells in this setting.

  View details for PubMedID 28824628

• DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft versus host disease. Blood Nishikii, H., Kim, B., Yokoyama, Y., Chen, Y., Baker, J., Pierini, A., Alvarez, M., Mavers, M., Maas-Bauer, K., Pan, Y., Chiba, S., Negrin, R. S. 2016

  Abstract

  CD4(+)Foxp3(+) regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft versus host disease (GVHD) in murine models of allogeneic hematopoietic stem cell transplantation (HCT). We recently demonstrated that a single treatment of the agonistic antibody to DR3 (Death receptor 3, αDR3) to donor mice resulted in the expansion of donor derived Treg and prevented acute GVHD, although the precise role of DR3 signaling in GVHD has not been elucidated. In this study, we comprehensively analyzed the immunophenotype of Treg after DR3 signal activation, demonstrating that DR3 activated Treg (DR3-Treg) had an activated/mature phenotype. Furthermore, the CD25(+)Foxp3(+) subpopulation in DR3-Treg showed stronger suppressive effects in vivo. Prophylactic treatment of αDR3 to recipient mice expanded recipient derived Treg and reduced the severity of GVHD, whereas DR3 activation in mice with ongoing GVHD further promoted donor T cell activation/proliferation. These data suggest that the function of DR3 signaling was highly dependent on the activation status of the T cells. In conclusion, our data demonstrated that DR3 signaling affects the function of Treg and T cell activation after alloantigen exposure in a time-dependent manner. These observations provide important information for future clinical testing using human DR3 signal modulation and highlight the critical impact of the state of T cell activation on clinical outcomes following activation of DR3.

  View details for PubMedID 27760760

• Cyclin-dependent kinase inhibitor p21, via its C-terminal domain, is essential for resolution of murine inflammatory arthritis ARTHRITIS AND RHEUMATISM Mavers, M., Cuda, C. M., Misharin, A. V., Gierut, A. K., Agrawal, H., Weber, E., Novack, D. V., Haines, G. K., Balomenos, D., Perlman, H. 2012; 64 (1): 141-152

  Abstract

  The mechanism responsible for persistent synovial inflammation in rheumatoid arthritis (RA) is unknown. Previously, we demonstrated that expression of the cyclin-dependent kinase inhibitor p21 is reduced in synovial tissue from RA patients compared to osteoarthritis patients and that p21 is a novel suppressor of the inflammatory response in macrophages. The present study was undertaken to investigate the role and mechanism of p21-mediated suppression of experimental inflammatory arthritis.Experimental arthritis was induced in wild-type or p21-/- (C57BL/6) mice, using the K/BxN serum-transfer model. Mice were administered p21 peptide mimetics as a prophylactic for arthritis development. Lipopolysaccharide-induced cytokine and signal transduction pathways in macrophages that were treated with p21 peptide mimetics were examined by Luminex-based assay, flow cytometry, or enzyme-linked immunosorbent assay.Enhanced and sustained development of experimental inflammatory arthritis, associated with markedly increased numbers of macrophages and severe articular destruction, was observed in p21-/- mice. Administration of a p21 peptide mimetic suppressed activation of macrophages and reduced the severity of experimental arthritis in p21-intact mice only. Mechanistically, treatment with the p21 peptide mimetic led to activation of the serine/threonine kinase Akt and subsequent reduction of the activated isoform of p38 MAPK in macrophages.These are the first reported data to reveal that p21 has a key role in limiting the activation response of macrophages in an inflammatory disease such as RA. Thus, targeting p21 in macrophages may be crucial for suppressing the development and persistence of RA.

  View details for DOI 10.1002/art.33311

  View details for Web of Science ID 000298598100018

  View details for PubMedID 21898359

  View details for PubMedCentralID PMC3253189

• Quality of life and depression assessment in nevoid basal cell carcinoma syndrome INTERNATIONAL JOURNAL OF DERMATOLOGY Shah, M., Mavers, M., Bree, A., Fosko, S., Lents, N. H. 2011; 50 (3): 268-276

  Abstract

  Nevoid basal cell carcinoma syndrome (NBCCS) is a rare genetic disease which causes a variety of dermatological lesions, especially basal cell carcinomas (BCCs), often on the face, neck, and head.Persons attending a national NBCCS support group meeting were asked to participate in survey-based assessments of quality of life and depressive symptoms. Inclusion criteria required a self-reported NBCCS diagnosis, voluntary agreement to participate, and age over 18 years. Exclusion criteria included cognitive impairment. Skin-related quality of life was assessed with Skindex-29, completed by 32 participants. Depressive symptomatology was determined with the Center for Epidemiological Studies Depression Scale (CES-D), completed by 18 participants. Sociodemographic, medical, and social variables were also analyzed.Median Skindex-29 scores for the emotions, symptoms, and functioning scales were 42.50, 32.14, and 28.13, respectively (means: 41.17, 37.05, and 29.30, respectively). These scores were slightly higher than those observed in patients with neurofibromatosis type 1, a similar genetic disease with skin symptoms. The CES-D scores (median = 15.50, mean = 17.50) suggested that 50% of participants had significant depressive symptomatology. Variables showing moderate associations with the scores included diet, number of affected family members, and treatment type. Interestingly, the number of BCCs had no effect.Nevoid basal cell carcinoma syndrome impacts the quality of life of its subjects in a similar manner to other genodermatoses. Depressive symptoms are particularly prevalent. Several demographic, medical, and social characteristics affect these outcomes. Thus, the psychological impact of this disorder should be evaluated in the course of considering the care of persons with NBCCS.

  View details for DOI 10.1111/j.1365-4632.2010.04658.x

  View details for Web of Science ID 000287587700004

  View details for PubMedID 21342158

• Bim-Bcl-2 Homology 3 Mimetic Therapy Is Effective at Suppressing Inflammatory Arthritis Through the Activation of Myeloid Cell Apoptosis ARTHRITIS AND RHEUMATISM Scatizzi, J. C., Hutcheson, J., Pope, R. M., Firestein, G. S., Koch, A. E., Mavers, M., Smason, A., Agrawal, H., Haines, G. K., Chandel, N. S., Hotchkiss, R. S., Perlman, H. 2010; 62 (2): 441-451

  Abstract

  Rheumatoid arthritis (RA) is a destructive autoimmune disease characterized by an increased inflammation in the joint. Therapies that activate the apoptotic cascade may have potential for use in RA; however, few therapeutic agents fit this category. The purpose of this study was to examine the potential of Bim, an agent that mimics the action of Bcl-2 homology 3 (BH3) domain-only proteins that have shown success in preclinical studies of cancer, in the treatment of autoimmune disease.Synovial tissues from RA and osteoarthritis patients were analyzed for the expression of Bim and CD68 using immunohistochemistry. Macrophages from Bim(-/-) mice were examined for their response to lipopolysaccharide (LPS) using flow cytometry, real-time polymerase chain reaction analysis, enzyme-linked immunosorbent assay, and immunoblotting. Bim(-/-) mice were stimulated with thioglycollate or LPS and examined for macrophage activation and cytokine production. Experimental arthritis was induced using the K/BxN serum-transfer model. A mimetic peptide corresponding to the BH3 domain of Bim (TAT-BH3) was administered as a prophylactic agent and as a therapeutic agent. Edema of the ankles and histopathologic analysis of ankle tissue sections were used to determine the severity of arthritis, its cellular composition, and the degree of apoptosis.The expression of Bim was reduced in RA synovial tissue as compared with controls, particularly in macrophages. Bim(-/-) macrophages displayed elevated expression of markers of inflammation and secreted more interleukin-1beta following stimulation with LPS or thioglycollate. TAT-BH3 ameliorated arthritis development, reduced the number of myeloid cells in the joint, and enhanced apoptosis without inducing cytotoxicity.These data demonstrate that BH3 mimetic therapy may have significant potential for the treatment of RA.

  View details for DOI 10.1002/art.27198

  View details for Web of Science ID 000279432100022

  View details for PubMedID 20112357

• Intracellular signal pathways: potential for therapies. Current rheumatology reports Mavers, M., Ruderman, E. M., Perlman, H. 2009; 11 (5): 378-385

  Abstract

  Drawbacks to current therapies for rheumatoid arthritis and the high cost of many of these drugs have lead to the investigation of novel approaches for treatment of this disease. One such tactic is the targeting of proteins involved in intracellular signal transduction. Inhibitors of p38 kinase have largely failed in clinical trials, due to both lack of efficacy and adverse events. The degree of adverse events may reflect off-target effects or, conversely, may be a mechanism-related event subsequent to successful inhibition of p38. Drugs targeting Janus kinases or spleen tyrosine kinase have shown greater success in clinical trials. A thorough analysis of specificity, as well as publication of both positive and negative results, must be the goal of continuing trials of these and other inhibitors of signal transduction molecules. The success of many clinical trials in this novel class of drugs provides optimism that more cost-effective and improved therapies will soon be available.

  View details for PubMedID 19772834

• The CDK domain of p21 is a suppressor of IL-1 beta-mediated inflammation in activated macrophages EUROPEAN JOURNAL OF IMMUNOLOGY Scatizzi, J. C., Mavers, M., Hutcheson, J., Young, B., Shi, B., Richard, M. P., Eric, M. R., Samways, D. S., Corbett, J. A., Egan, T. M., Perlman, H. 2009; 39 (3): 820-825

  Abstract

  Significant morbidity and mortality can be attributed to inflammatory diseases; therefore, a greater understanding of the mechanisms involved in the progression of inflammation is crucial. Here, we demonstrate that p21((WAF1/CIP1)), an established suppressor of cell cycle progression, is a inhibitor of IL-1beta synthesis in macrophages. Mice deficient in p21 (p21(-/-)) display increased susceptibility to endotoxic shock, which is associated with increased serum levels of IL-1beta. Administration of IL-1 receptor antagonist reduces LPS-induced lethality in p21(-/-) mice. Analysis of isolated macrophages, which are one of the central producers of IL-1beta, reveals that deficiency for p21 led to more IL-1beta mRNA and pro-protein synthesis following TLR ligation. The increase in IL-1beta pro-protein is associated with elevated secretion of active IL-1beta by p21(-/-) macrophages. siRNA-mediated knockdown of p21 in human macrophages results in increased IL-1beta secretion as well. A peptide mapping strategy shows that the cyclin-dependent-kinase (CDK)-binding domain of p21 is sufficient to reduce the secretion of IL-1beta by p21(-/-) macrophages. These data suggest a novel role for p21 and specifically for the CDK-binding domain of p21((WAF1/CIP1)) in inhibiting inflammation.

  View details for DOI 10.1002/eji.200838683

  View details for Web of Science ID 000264683500030

  View details for PubMedID 19189309

  View details for PubMedCentralID PMC2734089

• Cardiac conduction abnormalities and congenital immunodeficiency in a child with Kabuki syndrome: Case report BMC MEDICAL GENETICS Shah, M., Bogucki, B., Mavers, M., deMello, D. E., Knutsen, A. 2005; 6

  Abstract

  Since it's recognition in 1981, a more complete phenotype of Kabuki syndrome is becoming evident as additional cases are identified. Congenital heart defects and a number of visceral abnormalities have been added to the typical dysmorphic features originally described.In this report we describe the clinical course of a child diagnosed with Kabuki syndrome based on characteristic clinical, radiological and morphologic features who died of a cardiac arrhythmia at 11-months of age. This infant, however, had abnormal pulmonary architecture and alterations in his cardiac conduction system resulting in episodes of bradycardia and asystole. This child also had an immunological phenotype consistent with common variable immunodeficiency. His clinical course consisted of numerous hospitalizations for recurrent bacterial infections and congenital hypogammaglobulinemia characterized by low serum IgG and IgA but normal IgM levels, and decreased antibody levels to immunizations. T-, B- and NK lymphocyte subpopulations and T-cell function studies were normal.This child may represent a more severe phenotype of Kabuki syndrome. Recurrent infections in a child should prompt a thorough immunological evaluation. Additionally, electrophysiology testing may be indicated if cardiopulmonary events occur which are not explained by anatomic defects.

  View details for DOI 10.1186/1471-2350-6-28

  View details for Web of Science ID 000231424200001

  View details for PubMedID 16042804