Diabetes (IDDM) results from the immune mediated destruction of the pancreatic islets by autoreactive T lymphocytes. Recent work has demonstrated that the pathogenic process can be counter-regulated by localized delivery of interleukin 4 (IL-4). However the mechanism mediating this protection is not fully understood. We seek to understand the pathway mediating the regulation of disease by IL-4, and enhance our understanding of the actions of regulatory cytokines in general. In the original application we put forth three working hypotheses to explain the regulation of IDDM that we observed by IL-4. During the funding period, extensive studies were performed to delineate between these mechanisms and we have found strong experimental support for one of these three hypotheses. Specifically, we believe that IL-4 acts through APC, to alter the expression of costimulatory molecules, which ultimately reshapes the peripheral T cell repertoire. In this renewal application we seek to mechanistically expand these studies, to fully understand the molecular basis of these changes on specific peripheral T cell subsets. We hypothesize that IL-4 induces altered T cell priming resulting in both expansion and contraction of specific subpopulations within the T cell repertoire, leading to a diminishment of overall pathogenicity, This will be tested in aims #1 and 2 of the renewal application where expansion and cell death, mediated by APCs, will be defined at a molecular level. Lastly, our data also suggests a second level of counter-regulation arising directly from the pancreatic tissue. Therefore, we will also test the hypothesis that IL-4expression alters the pancreatic microenvironment, affecting the bioavilabillty of factors that govern the survival and expansion of T cells locally. This work will explore changes in the cell matrix and its association with immunoregulatory cytokines that can critically affect T cell survival, and the role of cell survival in the pathogenesis of autoimmune diabetes as a more generalized question. The studies proposed should greatly expand our understanding of counter-regulatory forces in vivo, allowing the use of these molecules as immunotherapeutic agents due to a greater knowledge of the mechanisms involved in protection.
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