The overall objective of this Program Project is to develop means of preventing the immunologic destruction of the beta cells in the islets of Langerhans that leads to insulin dependent diabetes mellitus (IDDM). To achieve this goal, we will use molecular and cellular immunologic techniques to understand the process that leads to beta cell destruction. Our Program focusses on mechanisms of pathogenesis and immune regulation of the process rather than descriptive studies of immunologic phenomenon. The members of the Program include 5 highly qualified Project Directors with diverse but related interests who form an interactive cohesive group. The approaches to be pursued are novel, but in all cases, offer the possibility for intervention which may result in prevention or reversal of the diabetic state. The specific areas include: 1) Co-stimulatory signals that activate diabetogenic T cells and regulate their destruction of islet cells. Attention will be directed towards the B7/CD28 family of molecules as well as novel co-stimulatory ligands, and the relationship between co- stimulatory signals and the outcome of the immune response will be studied: 2) Regulation of processing and presentation of islet antigens to T cells and control of the immune response by cells expressing MHC molecules: 3) Mechanisms of beta cell death including the involvement of members of the bcl-2 family on this event, and the control of the immune and autoimmune response by this process. The pursuit of the Project goals will be supported by an administrative core and 2 scientific core laboratories that will provide flow cytometry, immunohistochemistry an islet isolation services to the investigators. In a very real sense, this Program fulfills its goal as an interactive, synergistic, organization that cannot be represented by the individual components alone. Because of this Program, outstanding scientists from related but separate fields have directed their attention to studies of the pathogenesis and models of IDDM. Each of the projects in this Program depends on interactions with other Program members depends on interactions with other Program members, and these interactions, involving technical, methodological reagents, scientific expertise, and parallel experiments, will facilitate and enrich progress in each of the areas of study. The optimism with which we view these future interactions is founded on a past history of highly successful and productive collaborations between the Program participants. Thus, in summary, this Program project brings together outstanding immunologic scientists and focusses their efforts in interactive projects devoted to understanding, preventing, and treating beta cell destruction that leads to IDDM.