Avoidance of autoimmunity appears to rely on a carefully orchestrated series of activities involving an appropriate interplay between genetics, the environment, and components of both the innate and adaptive (acquired) immune systems. When this process fails, a variety of autoimmune disorders can arise;including type 1 diabetes where insulin producing pancreatic p cells are destroyed. Adaptive CD4'^ T helper (TH) cells orchestrate the nature and duration of immune responses through distinct properties of lineage-specific cell subsets (e.g., THI, TH17, regulatory T cells (Treg), etc.). The overall objective of Project 2 is to characterize the interplay between antigen presenting cells (APC) and TH subsets, identify their mechanistic contribution to the pathogenesis of TID, evaluate the potential of these cells to serve as markers for autoimmune disease activity. In addition, a major emphasis will be given to evaluate the contributions of specific candidate genotypes previously identified in genome wide association studies (GWAS), for their contribution to immune regulation (Project 2 - ILISRAP, TLRS;Project 1 - IFIHI). This project emanates from literature suggesting that patients with TID exhibit a remarkable loss of immunoregulation whose cellular contributors include proinflammatory APC, unstable and functionally defective Treg, and persistent T effector cells (Teff) that are refractory to regulation. Project 2 will test the hypothesis that in TID, CD4^ T cells are functionally defective and that the molecular &cellular basis for this defect resides in interactions between the innate and adaptive immune response (including dendritic cells, natural killer (NK) cells, & iNKT cells) as well as the balance between Teff and Treg subsets. We believe Project 2 finds marked innovation through the integrative approach afforded by the POI mechanism, the use of novel methodologies to isolate the cellular source of defects, the study of genetic loci underrepresented in TID research and quite importantly, our ability to explore lymphoid and pancreatic tissues and cells from the nPOD program.
Patients with TID, as well as those at risk for developing the disease, would benefit from this research in it's provision of an improved understanding of how and why the disorder develops. In addition. Project 2 holds the promise of providing improved biomarkers that better identify risk for developing TID, as well as novel therapeutics capable of preventing and/or reversing the disease.
|Haller, Michael J; Gitelman, Stephen E; Gottlieb, Peter A et al. (2016) Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes. Diabetes 65:3765-3775|
|Delitto, Daniel; Delitto, Andrea E; DiVita, Bayli B et al. (2016) Human pancreatic cancer cells induce a MyD88-dependent stromal response to promote a tumor-tolerant immune microenvironment. Cancer Res :|
|Seay, Howard R; Yusko, Erik; Rothweiler, Stephanie J et al. (2016) Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes. JCI Insight 1:e88242|
|Bian, Xiaofang; Wallstrom, Garrick; Davis, Amy et al. (2016) Immunoproteomic Profiling of Antiviral Antibodies in New-Onset Type 1 Diabetes Using Protein Arrays. Diabetes 65:285-96|
|Campbell-Thompson, Martha L; Kaddis, John S; Wasserfall, Clive et al. (2016) The influence of type 1 diabetes on pancreatic weight. Diabetologia 59:217-21|
|Babon, Jenny Aurielle B; DeNicola, Megan E; Blodgett, David M et al. (2016) Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes. Nat Med 22:1482-1487|
|Battaglia, Manuela; Atkinson, Mark A (2015) The streetlight effect in type 1 diabetes. Diabetes 64:1081-90|
|Haller, Michael J; Gitelman, Stephen E; Gottlieb, Peter A et al. (2015) Anti-thymocyte globulin/G-CSF treatment preserves Î² cell function in patients with established type 1 diabetes. J Clin Invest 125:448-55|
|Oleson, Bryndon J; McGraw, Jennifer A; Broniowska, Katarzyna A et al. (2015) Distinct differences in the responses of the human pancreatic Î²-cell line EndoC-Î²H1 and human islets to proinflammatory cytokines. Am J Physiol Regul Integr Comp Physiol 309:R525-34|
|Ulmer, Candice Z; Yost, Richard A; Chen, Jing et al. (2015) Liquid Chromatography-Mass Spectrometry Metabolic and Lipidomic Sample Preparation Workflow for Suspension-Cultured Mammalian Cells using Jurkat T lymphocyte Cells. J Proteomics Bioinform 8:126-132|
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