EFFECT OF MAJOR HISTOCOMPATIBILITY COMPLEX MATCHING ON THE DEVELOPMENT OF TOLERANCE TO PRIMARILY VASCULARIZED RENAL-ALLOGRAFTS - A STUDY INMINIATURE SWINE

Prevention of rejection and the induction of transplantation tolerance are two related bur separable phenomena that must both be considered in the analysis of the response to a transplanted organ. It is frequen tly hard to separate these phenomena in assessing che outcome of clini cal transplants, because patients are rarely studied in the absence of immunosuppressive agents. Use of our partially inbred miniature swine has permitted us to examine the effects of selective MHC matching on transplant survival, and the data indicate that matching has an effect on both phenomena. Prevention of early rejection with CyA was possibl e for all mismatches examined, although it was clearly more difficult with increasing degrees of mismatching. On the other hand, tolerance i nduction alter cessation of the immunosuppressive agent was dependent on presence of at least one matched MHC locus between the donor and re cipient, with complete class II matching appearing to be the most succ essful way of assuring long-term graft survival. It is also apparent f rom our data that although durable tolerance to primarily vascularized renal allografts could be induced across a variety of selective MHC d isparities, all cases involving a class II mismatch (ie, selective cla ss I matched or one-haplotype full MHC mismatched kidney allografts) u nderwent spontaneously reversible rejection crises during the early fo llow-up period. Such a clinical course might be unacceptable for human clinical trials, even though the transient renal dysfunction may refl ect events involved in tolerance induction rather than true rejection (Gianello et al. Immunol Rev 131:19, 1993.). Indeed, we do not yet kno w whether or not further immunosuppressive treatment at the times of s uch crises may prevent rather than facilitate the induction of toleran ce. On the other hand, in the case of selective two-haplotype class I mismatch, the regimen utilized was capable of inducing tolerance to re nal allografts in 100% of the recipients with minimal or no renal dysf unction throughout the follow-up period. Although the excellent result s achieved with current antirejection agents has led to debate about t he wisdom of HLA matching for cadaver transplants in terms of preventi ng rejection, our data would suggest that such matching might be of ev en greater importance for success of protocols in which attempts are m ade to induce transplantation tolerance. Because class II antigens are less polymorphic than are class I antigens, mismatching for class I a ntigens may be achievable for cadaver donor transplantation, and may p rovide the first situation in which these principles can be applied to clinical trials.