Transplantation of organs is an important form of therapy for the treatment of end-stage kidney, liver and heart disease. Unfortunately, current clinical practice relies on potent, non-specific immunosuppressive drugs which are neither totally successful in preventing rejection nor free from complications. In order to develop more specific and effective therapies it is imperative that we improve our understanding of the process of allograft rejection and develop novel strategies for tolerance induction. The proposed research will develop and assess a non-myeloablative protocol to induce indefinite allograft survival and tolerance in a murine model and thus facilitate the rational application of such intervention to clinical transplantation. Our central hypothesis is that the combination of donor bone marrow transfusion and CTLA4-Ig treatment will provide a clinically relevant means to prolong allograft survival indefinitely and induce transplantation tolerance. We propose to test this hypothesis in the murine system because it provides both a vascularized cardiac allograft model in which to refine this treatment protocol and unique cellular and molecular tools to analyze the immunologic mechanisms. Specifically, in this model we will: (1) define the optimal protocol for the induction of donor specific transplantation tolerance using the combination of CTLA4- Ig and donor bone marrow transplant (BMT); (2) use molecular, immunohistological, and flow cytometric techniques to characterize the development and nature of hematopoietic chimerism in CTLA4-Ig/BMT transplant recipients; (3) define the role of hematopoietic chimerism in transplantation tolerance induced by CTLA4-Ig/BMT: (4) determine the critical cell population required for the prolongation of allograft survival using bone marrow transplants either deficient in or enriched for specific cell lineages; (5) test the efficacy of administering the critical cell population for the establishment of chimerism and transplantation tolerance; (6) analyze the specific alterations in the recipient T cell population which are associated with CTLA4-Ig/BMT induced tolerance. The development and mechanistic analysis of the optimal CTLA4-Ig/BMT protocol for tolerance induction in the murine model will allow this knowledge to be applied large animal transplant models to test the ability of CTLA4-Ig/BMT to prolong allograft survival prior to application to clinical transplantation.
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