Pancreatic tissue grafting is by far the most physiological therapeutic solution to the insulin deficiency of diabetes. Both pancreas and islets of Langerhans have been transplanted successfully in humans and in animals models resulting in full normalization of glucose homeostasis. However, the chronic immunosuppression needed to avoid immunological rejection appears to be toxic to the islets and adds the risk of lymphoproliferative disease. The future lies in developing alternative strategies to the current immunosuppressive drugs. With the long-term objectives of a) prolonging islet cell graft survival, and b) maintaining the graft without the use of immunosuppression, we propose to examine the effect of donor CD34+ marrow cell implantation on islet cell transplantation in an animal model. Because of the close phylogenetic similarity between macaques and humans, we have selected a macaque model with well-defined genetic markers to study these objectives. Aim 1. To determine whether donor marrow-derived CD34+ stem cell rich fractions, including hematopoietic stem cells, contribute to graft survival of allogeneic donor islets transplanted into the thymus. Aim 2. To determine whether donor antigen presenting cells (APCs) are a requirement for cellular transplant tolerance. Aim 3. To investigate the effects of intrathymic versus peripheral administration of donor marrow-derived CD34+ stem cell-rich fractions in achieving and maintaining lymphohematopoietic microchimerism. Aim 4. To examine whether recipient exposure to selected third party histocompatibility sequence motifs shared with the islet donor ("motif matching") is adequate to prolong allogeneic islet graft survival. Aim 5. To compare the efficacy of "motif matching" versus "traditional matching" between third party human stem cell donors and islet donors in achieving graft survival of transplanted allogeneic islets. Hence, the long term goal of this proposal is to establish a stable and prolonged microchimerism inducing donor specific tolerance to avoid use of an immunosuppressive regimen for islet allograft survival.