ISLET DESTRUCTION IN THE ETIOLOGY OF DIABETES

With mounting evidence of autoimmune mechanisms in the pathogenesis of Type I insulin-dependent diabetes mellitus (IDDM), and the availability of the BB/w rat model of IDDM, it has become possible to formulate and test strategies in using specific immunological techniques in clarifying and modulating this disease. With out continued interest in islet transpolantation as a potential cure for IDDM, we have been investigating the potential autoimmune destruction of native and transplanted islets. Our in vivo preliminary results show that MHC matched and mismatched islets transplanted into acutely diabetic BB/w rats are equally destroyed; evidence that the autoimmune mechanism leading to initial expression of IDDM is active and not restricted by the MHC. We have expanded this work to show that cytotoxic T lymphocytes (CTL) against islet cells can be derived from the acutely diabetic BB/w rat at the non-clonal and clonal levels. They appear in vitro to be specific for islet cells and not to be restricted by the MHC. Our ability to generate these cytotoxic cell lines specific for islet cells (beta cells?) makes it possible to formulate and execute the following series of experiments to attempt specific immunological modulation of IDDM in the BB/w rat model, not only as a means of modulating the native disease, but as a method of protection against autoimmune destruction of transplanted islets. We, therefore, propose 1) to generate islet beta-cell reactive cytolytic and non-cytolytic T cell clones from the acutely diabetic BB/w rat and to define their specificity toward endocrine (beta-cell, non beta-cell) and non-endocrine cells; 2) to use these beta-cell specific T effector cell lines in the induction of IDDM in diabetic prone and non-diabetic prone BB/w rats and to investigate the possible role that such cytolytic and non-cytolytic beta-cell specific T cells may play in the manifestation of diabetes mellitus; 3) to test the possibility of using the T effector cells in an attenuated form (Gamma irradiated) to vaccinate diabetic prone BB/w rats against the development of IDDM; and 4) to generate monoclonal antibodies (MAb) recognizing the t cell receptors of the anti-beta-cell specific CTL's and possibly use these MAb's in the modulation of the onset and progression of IDDM in the BB/w rat.