Liver transplant tolerance: Mechanistic insights from animal models, with particular reference to the mouse

Abstract

W ith some exceptions, organ allograft survival in humans is dependent on the prolonged use of nonspecific immunosuppressants to prevent rejection. Despite the remarkable improvements in graft survival and quality of life that have been achieved in the past 15 to 20 years because of the introduction of cyclosporine and, more recently, tacrolimus, many adverse side effects continue to be associated with the use of immunosuppressive agents, including increased risks of opportunistic infection, malignancy, and end-organ toxicities. Strenuous efforts thus continue to be made to identify methods of inducing drug-free, permanent, donor-specific unresponsiveness (tolerance), which preserve overall host immunocompetence with minimal attendant side effects. Much can to be learned from animal models. Remarkably, between some outbred pigs and in certain inbred rat and most mouse strain combinations, liver allografts are accepted across major histocompatibility barriers without the need for immunosuppressive therapy. It is not completely understood why this occurs frequently with the liver (and only exceptionally for the heart and kidney) in certain mouse strain combinations, but some insight has been gained into possible mechanisms. A fuller understanding of the mechanistic basis ofwhy livers are accepted, and why the liver induces systemic, donor-specific tolerance, is likely to have an important bearing on the design of future immunosuppressive strategies. This article focuses on recent knowledge acquired with animal models, with special reference to the mouse, in which orthotopic liver transplantation was fist accomplished successfully in 1991 .I