Cyclosporine has been shown in animal studies and in clinical trials to be an effective immunosuppressive agent. It prolongs allogragt survival with less side effects than other agents and has now been approved for clinical use. However serious questions remain. Toxic effects on renal function have been noted in clinical trials and the mechanism of action of cyclosporine in suppressing immune reactivity is poorly understood. The goal of this proposal is a systematic study of the toxicologic and immunologic effects of cyclosporine in the rabbit. The rabbit is selected because the toxic effect of cyclosporine may be more similiar to that in man than in other experimental animals, the rabbit is large enough to permit grafting of solid organs such as the kidney, and the immune response of the outbred rabbit is a more realistic model than that of inbred experimental animals. In preliminary experiments the effect of different doses and different routes of cyclosporine on rabbits will be analyzed by detailed studies of renal and liver function, and correlated to morphologic changes. The effects of cyclosporine on lymphoid organs and lymphoid cell function will be analyzed in a series of in vivo and in vitro studies. The immunologic and toxic effects of cyclosporine will then be tested in rabbits with renal grafts across different degrees of histocompatibility. Finally the effect of cyclosporine on experimental virus induced tumors and experimental syphilis, both having substantial immunopathologic components, will be determined. These studies should contribute greatly to our understanding of the mechanism of toxicity and immunosuppression of a drug which is being used increasingly for clinical application.
