Spontaneous acceptance or rejection of orthotopic liver transplants in outbred and partially inbred miniature swine

Background. Results of clinical liver transplantation have shown that rejec tion and loss of human liver allografts occurs despite immunosuppression, b ecause genetic disparity and liver immunogenicity remain a matter of contro versy, we reexamined the fate of outbred liver allografts without immunosup pression and used partially inbred miniature swine, in which the genetics o f major histocompatibility complex (MHC) antigens have been characterized a nd can be controlled. Methods. Orthotopic liver transplantation was performed between pairs of ou tbred domestic farm pigs and between pairs of inbred miniature swine with g enetically defined major histocompatibility (SLA) loci. A passive splenic a nd vena caval to jugular vein shunt with systemic heparinization prevented hypotension during the anhepatic phase. Immunological responses were monito red by mixed lymphocyte culture (MLC), CML, skin graft rejection, liver bio psies, and serial serum chemistries. Results, Median survival of technically successful liver allografts between pairs of outbred pigs (n=20) was 38 days and between partially inbred swin e matched at the SLA locus (n=17) was 79 days. MLC responsiveness did not c orrelate with the development of rejection. Five of 20 (25%) outbred pigs a nd 6 of 17 (35%) MHC matched inbred miniature swine survived more than 100 days. In the long-term survivors, donor, but not third party, MHC matched s kin graft survival times were prolonged. In contrast, all SLA-mismatched in bred recipients (n=26) died rapidly from massive liver rejection, with a me dian survival time of 9 days. In these rejecting animals, the marked MLC re sponsiveness to donor lymphocytes evident pretransplant diminished rapidly after transplantation, but an undiminished PHA responsiveness and a blunted third party MLC response persisted. Conclusion The length of survival and the degree and incidence of rejection were similar in outbred pigs and in SLA-matched inbred miniature pigs, ind icating that the outbred animals were, therefore, probably closely related and shared relevant genes, However, survival was significantly shortened an d liver allograft rejection was accelerated in SLA-mismatched inbred swine. These results indicate that major histocompatibility differences play an i mportant role in the rejection of liver allografts, as is true for other va scularized grafts in the unimmunosuppressed recipient. The development of l iver allograft rejection across non-MHC differences is variable and, when p resent, appears to be a chronic process.