Study of the role of Islets of Langerhans in Autoimmune Diabetes

The work conten of this project is centered around three objectives. Objective 1 test the hypotesis that a primary islet defect leads to hyperfunction/mega-slets causing infiltration by antigen presenting cells and increased B-cell antigen presentation. generation of autocreative T cells is the net result; probes are developed to identify them and the relevant antigens. it is thugh that B-cells are destroyed only late during the long-term immune process through cytokine-induced NO production; the molecular mechanisms of the regulation of the iNOS gene are investigate. Objective 2 aims at preventing reduction in B-cell mass. This is done by interfering with iNOS induction, helping other defence mechanisms, and inducing B-cell resistance and growth by specific factors, i.a. REG protein. Objectives 3 aims to replace destroyed B-cells by engineered cells. Methods are developmed for conditional immortalization of B-cells to obtain differntiated cell lines. Molecules that physiologically control insulin gene expression are cloned, and methods developed for transferring these into surrogate B-cells towards transplantation of glucose-sensitive insulin-producing cells. These objectives will be achieved by the research plan and specific tasks described below.