This Program Project grant is entitled "Pathophysiology and Immunotherapy of NOD Disease". There are five interrelated projects that concern 1) understanding pathophysiologic events which lead to insulitis and diabetes in NOD mice; 2) attempt to develop immunotherapeutic regimens to block ultimate beta cell destruction, or 3) to replace islet tissue via transplantation. Project I will attempt to understand the mechanisms involved in a form of transplantation tolerance induction: the use of monoclonal antibodies reactive with the T cell subset bearing the CD4 differentiation antigen. Recent data from Dr. Fathman's laboratory have supported the concept that T cell clonal anergy results from this form of immunotherapy. In collaboration with Dr. Gerald Crabtree, they will explore potential mechanisms of anergy as they relate to transplantation tolerance (Project I) or to potential forms of immunotherapy (Project V). Project II brings Dr. Mark Davis' expertise in T Cell receptor characterization to the area of diabetes research. Dr. Davis plans to collaborate with Dr. Fathman in isolation and characterization of T lymphocytes which are involved in early inductive events leading to insulitis and/or later events leading to beta cell destruction and overt hyperglycemia. In Project III, Dr. Irving Weissman brings his expertise in identification and isolation of hematopoietic stem cells to the area of diabetes experimentation. This project interrelates with Project I to develop new methodologies to allow transplantation tolerance induction for islet allografts. Additionally, Dr. Weissman intends to ask whether stem cell reconstitution will result in blockade of disease induction or perpetuation in NOD mice as has been previously demonstrated by allogeneic bone marrow transplantation. Project IV deals with the development of transgenic NOD mice in which putative autoantigens, previously identified as potentially involved in pathophysiologic events in NOD disease, will be used to develop transgenic models. The hypothesis to be tested is that anergy to such transgenes will develop and demonstrate whether the transgene product is involved in the development of NOD disease. Finally, Project V is an attempt to directly identify those T cells involved in early inductive events of inflammatory insulitis, as well as later sequelae leading to beta cell destruction. All five of these projects interrelate within the context of this Program Project Grant and are dedicated to understanding pathophysiologic events leading to insulitis and/or diabetes in NOD mice and to asking whether novel forms of potential immunotherapy might either allow transplantation of islets into diabetic mice or prevent beta cell destruction in NOD mice prior to overt hyperglycemia.