Recruitment of leukocytes into the pancreatic islets of Langerhans is a necessary step in the pathogenesis of Type I diabetes. Experimental evidence implicates chemokines in the regulation of leukocyte migration into the islets. Chemokines are expressed by islet cells in culture and within the pancreatic islets in animal models of diabetes. Moreover, as shown by our group and others, islet-specific transgenic expression of certain chemokines is sufficient to induce recruitment of lymphocytes and macrophages into the islets. Our recent work has shown that chemokines are critical for development of diabetes. We hypothesize that CCL2 and its receptor are critical for initial influx of monocytes and DC into the islets. This process can on itself lead to islet destruction if completely dysregulated. We hypothesize that the trafficking of DC carrying autoantigens produced during the initial inflammatory process into the peripancreactic lymph nodes is dependent on CCR7. We also hypothesize that trafficking of naove autoreactive T cells into the peripancreactic lymph nodes is dependent on CCR7. Together these processes may be critical for priming and expansion of autoreactive T cells. Finally, we hypothesize that reactivation of autoreactive T cells may happen within lymphoid-like structures generated by expression of CCL21 within the islets during the period preceding development of diabetes. In this proposal we will study the role of CCL2-CCR2 in the development of insulitis and diabetes and define the role of CCL21-CCR7 in the development of autoimmune diabetes.
Type I (or insulin-dependent) diabetes afflicts millions of people worldwide;one important component of the pathogenesis of this disease is the presence of inflammatory cells in the pancreas. The inflammatory cells eventually destroy cells producing insulin, a hormone that is important for the entry of sugars into cells - as the levels of insulin go down, the levels of sugar in the bloodstream increase, causing disease;we have identified factors that control the entry of inflammatory cells into the pancreas, suggesting that specific drugs may be designed to block such factors. We anticipate that blocking entry of inflammatory cells into the pancreas will prevent destruction of the insulin-producing cells;our work may thus prompt the generation of novel treatments for Type I diabetes.
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