Allograft rejection is a major problem in organ or cell transplantation. Development of a method for induction of specific tolerance to allografts, without the need for immunosuppression, would be a major advance in transplantation biology. Recently, adult rodent models of transplantation tolerance has been developed in several laboratories. Long-term tolerance to allogeneic hepatocytes has been induced in recipient genetically analbuminemic (NAR) rats, by intrathymic inoculation of donor splenocytes along with ablation of peripheral lymphocytes by injection of anti lymphocyte serum. Hepatocytes from the donor strain transplanted into NAR recipients 2-3 weeks later, were permanently accepted. Mechanisms by which tolerance is induced in these animals are unclear. The tolerance may be mediated by clonal deletion or clonal anergy of alloreactive T cells, or by the development of a negative regulatory mechanism. It is unknown whether persistence of donor type lymphocytes along with the recipient type cells (microchimerism) in the thymus or in the periphery is required to maintain tolerance, or secretion of soluble factors or recirculating cells from the graft are sufficient. This project aims to elucidate the mechanisms of allograft tolerance in a model system in which normal hepatocytes from allogeneic donors are transplanted into NAR recipients. Specifically, we will evaluate the possible role of donor microchimerism in the induction or maintenance of tolerance, identify of the type of cells that are involved in tolerance induction, determine whether tolerance can be induced or maintained by soluble MHC class l, and assess the possible role of regulatory T cells in tolerance induction or maintenance. Successful elucidation of the mechanisms of allograft tolerance should provide key information towards the translation of animal models to the realm of human transplantation.
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