The long range goal of this grant application is to study the process of pancreatic beta cell destruction which is a primary characteristic of both human and experimental diabetes. The spontaneous diabetic syndrome in the BioBreeding/Worcester (BB/Wor) rat presents an unique model of insulin-dependent diabetes in which to study the cell-mediated autoimmune destruction targeted to the beta cell. The hypothesis to be tested is that the autoimmune lesion of diabetes is beta-cell specific and. in part. mediated by an effector population of lymphoid cells which infiltrate and destroy pancreatic beta cells. To address this problem. experiments are proposed which utilize a novel, established islet transplantation system whereby the interaction of infiltrating mononuclear cells and islet beta cells can be examined during the course of the insulates lesion. Specifically, the following research aims will be addressed: 1.) can the lymphocytes which infiltrate pancreatic islet grafts be maintained and cloned in vitro? 2.) do the T cell lines derived from infiltrating lymphocytes respond in vivo to antigenic stimulation? 3.) do T cell lines from islet grafts represent a homogeneous population and is their function determined by MHC class or class II restriction patterns? do T cell lines express a cytotoxic function? 4.) do the T cell Tines possess a diabetogenic potential in vivo? The focus of this specific aim is to evaluate a possible role for the T cell lines to induce disease and the cellular events leading to the disease process. The elucidation of the mechanisms involved in the autoimmune destruction of pancreatic beta cells is important clinically since the beta cell is the primary site of pathology in both human and experimental diabetes. The methodologies to be used are primarily immunologic in nature and include: tissue culture, monoclonal antibodies, mixed lymphocyte and cytotoxicity assays, adoptive transfer, immunohistochemistry, flow cytometry, histology, and phase and light microscopy.
