Type 1 diabetes (T1D) results from the autoimmune T lymphocyte mediated destruction of the insulin producing beta cells in the pancreas. Multiple daily insulin injections are a lifesaving therapy for diabetic patients, they are not a cure. In order to cure T1D we must first identify the self-reactive T cells, and secondly we must remove them. Until recently identifying the cells has been a very difficult task. However, recent advances in peptide-MHC tetramer technology have allowed us to identify, track and interrogate individual CD4+ T lymphocyte clones in both mouse models and humans with type 1 diabetes. By having the tools and technology to study antigen specific T cells during disease, we will be able to assess the breakdown in peripheral tolerance and examine therapeutic efficacy to selectively remove or silence these self-reactive T cells as a targeted cure. We have recently adapted a sensitive tetramer enrichment protocol allowing the identification and phenotyping of exceedingly rare CD4+ T cells of a specific peptide:MHCII complex. We hypothesize that class II MHC:peptide tetramer and enrichment techniques will provide a sensitive and robust method for determining the number and activation status of islet Ag-specific CD4+ T cells using clinically feasible samples from T1D patients. We further hypothesize that characterization of islet Ag-specific CD4 T cells using this approach will provide a useful biomarker reagent for T1D diagnosis and disease staging. Using this technology we will determine if peripheral tolerance is lost in diabetic patients and islet beta cell peptide epitopes become major targets of the immune system. We predict that individuals with new onset T1D will have more beta cell peptide:MHCII specific CD4+ T cells with an activated phenotype than non-diabetic individuals. With a better understanding of beta cell targets, we will be able to develop antigen specific approaches to selectively eliminate self-destructive T cells to cure diabetes.
This proposal is focused on understanding the mechanisms of peripheral immune tolerance to prevent self- reactive T cells from causing autoimmune diabetes. It will utilize innovative technology and enrichment approaches to identify and track self-reactive T cells during diabetes pathogenesis in human type 1 diabetic patients and utilize mouse models to understand tolerance mechanisms. Results from these studies could lead to novel methods for earlier diabetes diagnosis in humans and biomarkers to monitor immune function and therapeutic efficacy. The rationale for the proposed research is that with a better understanding of immune targets we will be able to develop translational approaches to selectively eliminate self-destructive T cells to cure diabetes.
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