Immune Tolerance in Mixed Chimeric Miniature Swine

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DESCRIPTION (provided by the applicant): Organ transplantation has become a widespread treatment for many patients with end-stage renal, hepatic, cardiac, and pulmonary disease. However, two major obstacles preventing greater successes are donor organ availability and treatment related complications including acute and chronic graft rejection. One attempt to avoid rejection is via the creation of specific transplantation tolerance, defined as elimination of the recipient?s immune response to a transplanted organ?s foreign antigens while leaving other host responses intact. Tolerance represents a major goal of modern transplant biology and is the focus of this research proposal. Specifically, the Sachs laboratory has developed a large animal model of tolerance using inbred miniature swine of known MHC haplotype. Using a non-myelosuppressive preparation and a high dose peripheral blood stem cell transplant protocol mixed lymphohematopoietic chimerism and transplant tolerance can be induced in these animals. When mixed chimeric swine undergo subsequent renal transplantation from the same donor of their stem cell transplant they accept a kidney graft with no exogenous -immunosuppression. This proposal will characterize the cellular nature of the immune tolerance generated in these animals. Special focus will be on study of an observed persistent sub-population of T-cells of donor origin in an effort to determine their origin, identity, and functional activity. Research design includes labeling of the donor inoculum prior to stem cell transplant to determine the heredity of the persistent T-cell population as well as CML and MLR assays to assess in vitro reactivity of these cells to the recipient. The importance of this population will be further assessed by transferring them to a matched naive animal to determine whether they will survive in this new host and perhaps create tolerance in that animal. Understanding on a cellular and molecular level the nature of this persistent donor T-cell population is crucial to understanding the nature of the transplant tolerance created in these remarkable animals.