Evaluation of the Immunosuppressant FK778 in Cynomolgus Monkeys

The immunosuppressant FK 778 is a synthetic malononitrilamide, pharmacologically related to leflunomide. Previous research done in rodents has shown that FK 778 is effective in preventing allograft rejection after solid organ transplantation. The aim of this study is to prove the immunosuppressive efficacy of FK 778 in non-human primates. Our team has shown that in vitro, FK 778 suppresses different immune functions of T cells from cynomolgus monkeys. The proposed study prove (i) the immunosuppressive effects of FK 778 on non-human primates in vivo, and (ii) the efficacy of FK 778 in preventing allograft rejection in a non-human primate transplant model. (i) In order to prove the immunosuppressive effects of FK 778 in vivo, cynomolgus monkeys will be given either single or multiple doses of the drug, and T cell proliferation and function will be assessed thereafter using flow cytometry. Plasma levels of FK 778 will be measured by HPLC, and a correlation between pharmacokinetics of the drug and the immunosuppressive effect (pharmacodynamics) will be sought. (ii) The efficacy of FK 778 in prevention of allograft rejection will be studied using a life supporting kidney transplant model in cynomolgus monkeys. Animals will be treated with FK 778 alone or in combination with a low, inefficient dose of tacrolimus (a currently used immunosuppressant). A third group of animals will be treated only with tacrolimus at a low, inefficient dosage (control group). Animals will be treated for 3 months; thereafter their grafts will be examined histologically. This should allow a conclusion about the value of FK 778 in helping prolong allograft survival and/or preventing allograft rejection. This study should help decide upon the value of using FK 778 in clinical transplantation.