INDUCTION OF TOLERANCE TO RENAL-ALLOGRAFTS ACROSS SINGLE-HAPLOTYPE MHC DISPARITIES IN MINIATURE SWINE

We have previously demonstrated that a 12-day course of cyclosporine A (CsA) leads to the induction of tolerance to renal allografts in 100% of recipients selectively mismatched at class I for both haplotypes, and in 71% of recipients selectively mismatched at class II for both h aplotypes, but in 0% of recipients mismatched for two haplotypes at bo th class I and class II. We have postulated that the mechanism by whic h tolerance is induced may therefore require matching for either class I or class II antigens. One might predict from this hypothesis that t olerance would also be induced in donor-recipient combinations sharing one full haplotype (e.g., AC-->AD), which mimics the clinically relev ant transplant combination of parent to offspring. We have therefore i nvestigated the effects of the CsA regimen on renal transplants in thi s combination. Without immunosuppression, such kidney allografts were uniformly rejected (n=12; 10.6+/-2.4 days). In contrast, a course of C sA (10-13 mg/kg/day) during the first 12 postoperative days induced lo ng-term acceptance of the allograft in 67% (4/6) of recipients. Some a cceptor animals also showed specific unresponsiveness to donor antigen s as measured by in vitro assays and by failure to develop anti-donor antibodies, Tolerance was confirmed in four of these animals by failur e to reject a second transplant SLA-matched to the first kidney donor without additional immunosuppression. These results suggest the feasib ility of inducing specific tolerance across a single-haplotype mismatc h in the majority of the cases, which could have clinical implications for living-related transplants.