MIXED XENOGENEIC CHIMERISM FOR ISLET XENOGRAFT TOLERANCE

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Type I diabetes is a systemic autoimmune process which results in destruction of the insulin-producing beta-cells and severe chronic complications. Islet transplantation is the most physiologic approach to replace pancreatic endocrine function in patients with Type I diabetes. This approach is currently limited by (1) rejection and (2) a shortage of organs. The induction of donor-specific transplantation tolerance across a species barriers has been suggested to overcome these limitations. The Principal Investigator recently reported the induction of donor-specific transplantation tolerance across a species disparity through the preparation of mixed xenogeneic chimeras (mouse + rat yields mouse). Recipients were specifically tolerant to the donor in vivo (skin graft) and in vitro, exhibited excellent survival, and resisted graft versus host (GVH) disease. The model for MIXED XENOGENEIC CHIMERISM will be applied TO INDUCE DONOR-SPECIFIC TRANSPLANTATION TOLERANCE TO PANCREATIC ISLET XENOGRAFTS (Specific Aim I). Bone marrow cells determine the susceptibility to autoimmune diabetes. Transplantation of bone marrow from normal animals into diabetes-prone recipients prevented the development of the disease. In Specific Aim II, the model for MIXED XENOGENEIC CHIMERISM WILL BE APPLIED TO REVERSE AUTOIMMUNE DIABETES IN DIABETIC NOD MICE (in conjunction with islet transportation) AND TO PREVENT THE DEVELOPMENT OF AUTOIMMUNE DIABETES before irreversible complications. SPECIFIC AIM II will extend these studies to achieve mixed xenogeneic chimerism using a nonlethal conditioning approach in anticipation of potential clinical application. Autoimmune disease is believed to result from a failure to adequately discriminate between self and non-self. Monoclonal antibodies directed against the variable portion (V) of the beta-chain of the T-cell receptor (Vbeta-TCR) are a powerful tool to follow the fate of potentially autoreactive T- lymphocytes developing in the thymus. Circumstantial evidence has been accumulating to strongly implicate peptides (SUPERANTIGENS) which bind to selected TCR-Vbeta families in autoimmune disease. Specific Aim IV will CHARACTERIZE THE PHENOTYPE OF EFFECTOR CELLS (INCLUDING VBETA REPERTOIRE) RESPONSIBLE FOR ISLET DESTRUCTION to analyze whether a superantigen effect is present in Type I Diabetes. The overall goals of this project is to treat diabetes, prevent the associated complications, and understand the mechanism underlying the autoimmunity.