Partially inbred miniature swine provide a unique large animal model for the studies of transplantation immunology. The availability of MHC homozygous and intra-MHC recombinant haplotypes have made it possible to study the effects of selective matching for class I and/or class II loci on parameters of transplantation immunity. Untreated recipients of renal allografts across two-haplotype class I or class II MHC barriers undergo acute rejection in all cases. During the previous project period the investigators established a treatment regimen involving a 12-day course of Cyclosporin A which led to tolerance in 100% of class I mismatched renal allografts and in 71% of class II mismatched renal allografts, but does not induce tolerance across two-haplotype full MHC barriers, suggesting that induction of tolerance by this regimen is facilitated by sharing of at least one MHC antigen. The major goal of the present proposal is to determine the mechanism by which such tolerance is induced and maintained. Specifically, the investigators will 1) determine whether the presence of the graft is required to maintain tolerance to renal allografts, and if so, for how long; 2) study the effect of thymectomy prior to or subsequent to kidney transplantation on induction of tolerance; and 3) study peripheral mechanisms involved in the induction and maintenance of tolerance which may explain the apparent requirement for MHC antigen sharing. Preliminary data are presented indicating that tolerance persists for at least one month, but not indefinitely after the renal allograft is removed, and that the thymus is involved in the mechanism by which tolerance is induced, since thymectomy leads to rejection crises and to less stable long-term tolerance. Both of these findings suggest that migration of donor cells and/or antigen to the thymus is involved in the mechanism of tolerance. The investigators will attempt to determine the precise localization of donor antigen during the induction and maintenance phases of tolerance by immunohistochemical and PCR techniques. It is hoped that an understanding of the mechanisms by which tolerance is induced to vascularized grafts in this model system will permit development of appropriate clinical protocols for induction of specific tolerance to organ allografts in human beings.
Showing the most recent 10 out of 58 publications
