Immunological mechanisms underlying T1DM pathogenesis

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Type 1 Diabetes Mellitus (T1DM) is an autoimmune disease resulting from the T cell mediated destruction of insulin-producing beta cells located in the pancreas. Current treatment, which includes insulin replacement by injection, frequent blood glucose monitoring, and dietary/exercise discipline, can prevent death from hormonal insufficiency, but is not curative and does not prevent long-term complications. Those complications include nerve damage and vascular deterioration (large and small blood vessels) resulting in damage to various organs, including the heart, brain, kidneys, and eyes. Life expectancy is shortened by an estimated one-third compared to similar individuals but without T1DM. This work, initiated several years ago at the Naval Medical Research Institute and further developed at the University of Ulm in Germany, has characterized a unique murine model of autoimmune diabetes using rat-insulin promoter (RIP)-CD80 transgenic mice (RIP-CD80 mice). These animals are predisposed to immune mediated beta cell destruction based on their beta cell-specific expression of the costimulatory molecule CD80. While RIP-CD80 mice rarely develop spontaneous diabetes (incidence 6.7%, compared to none of wild type mice), we have observed and have initially characterized the profound susceptibility these mice display to develop progressive islet infiltration and eventually insulin dependent diabetes mellitus (IDDM) following immunization with beta cell autoantigens (i.e. protein molecules that are expressed specifically by the pancreatic beta cells of these mice). For instance, these animals, unlike non-transgenic littermates, uniformly develop islet cell destruction and IDDM upon immunization with insulin precursors, a beta cell autoantigen strongly suspected to be involved in the pathogenesis of T1DM in humans. Hence, this laboratory's objective using the above mouse model can be summarized as follows:(1) We are preparing to identify self-antigens (Ag) that are thought to be important initial target Ag for the developing autoimmune response. For this purpose, we will simply immunize RIP-CD80 transgenic mice with the various candidate auto-antigenic molecules and then follow them for the development of Ag-specific T cell responses, insulitis, and diabetes.(2) We will study beta cell specific T cell responses in an adoptive transfer model where the primary sensitization of the autoreactive T cells will take place either in vitro, or by immunizing in vivo, as proposed in (1). These studies will focus on the mechanisms of the developing beta cell destructive immune responses, as described in 1) and 2), and will attempt to identify novel approaches to interfere with the ongoing immune responses.