By reversing autoimmune disease and inducing tolerance to donor pancreatic islets, the transplantation of diabetes-resistant bone marrow cells could lead to a potential cure for diabetes. Unfortunately, the transplantation of pancreatic islets and bone marrow harvested from cadaveric donors has not yet been exploited in man because of the unacceptable toxicity associated with myeloablative host conditioning needed to achieve engraftment and because of the complications associated with allo-BMT. We have recently succeeded in achieving lasting mixed chimerism, tolerance toward donor tissue and protection from diabetes in NOD mice using a relatively non-toxic, non-myeloablative conditioning regimen followed by transplantation of diabetes resistant bone marrow. Diabetic NOD mice in which bone marrow chimerism was established accepted donor islets and were cured of diabetes. The goal of this project is to evaluate the mechanisms by which donor bone marrow cells that express protective MHC and/or non-MHC encoded diabetes-resistant genes mediate protection from diabetes. The use of three strains of diabetogenic TCR transgenic NOD mice, conditioned with a non-myeloablative conditioning regimen as recipients of different donor bone marrow cells will help us define the role of anergy, deletion and suppression of both CD4+ and CD8+ diabetogenic T cells. Furthermore, we will evaluate if induction of mixed chimerism, induced by autologous bone marrow cells, which have been retrovirally-transduced with diabetes protective MHC class II genes, is sufficient to prevent diabetes. These studies will lead to a better understanding of MHC and non-MHC encoded gene mediation of resistance to diabetes. A detailed analysis of the mechanisms involved in this protection and tolerance induction will allow development of a more specific approach, and thus bring us closer to clinical application.