DEVELOPMENT OF TOLERANCE TO CLASS-II MISMATCHED RENAL-TRANSPLANTS AFTER A SHORT-COURSE OF CYCLOSPORINE THERAPY IN MINIATURE SWINE

Our laboratory has reported previously spontaneous acceptance of class II-matched, single haplotype (but not 2 haplotype), class I-mismatche d renal allografts in miniature swine. All class II-mismatched animals rejected acutely regardless of class I matching. We have also demonst rated recently that a short course of high dose (10 mg/kg/day for 12 d ays) CsA uniformly induces donor-specific tolerance to 2-haplotype, cl ass I-mismatched renal allografts. The survival of 2-haplotype, fully MHC mismatched renal allografts was prolonged by the same treatment, b ut tolerance was not induced, as all animals rejected eventually. We h ave now tested this short course of immunosuppressive therapy for its effect on renal allografts mismatched selectively for 2 haplotypes at class II. We have observed long-term graft survival in 5 of 7 animals under these conditions. Each of the 5 acceptor animals was demonstrate d to be specifically tolerant by its response either to donor-matched skin grafts or to a second donor-matched kidney transplant without fur ther immunosuppression. These data suggest the existence of a common p athway for induction of specific transplantation tolerance to MHC anti gens when these antigens are recognized on vascular endothelium under conditions of altered cytokine production. They also suggest that tole rance induction under these conditions requires matching for either cl ass I or class II antigens, which may have implications for the mechan ism by which peripheral tolerance is induced, as well as practical imp lications for the extension of these results to potential clinical pra ctice.