Development of a new immunosuppressive strategy by targeting pyrimidine synthesis

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Leflunomide is a strong immunosuppressant that exerts its effect by blocking de novo pyrimidine synthesis. It has been shown that Leflunomide is a useful immunosuppressive agent in clinical trials of autoimmune diseases. However, due to the drug's long half-life, Leflunomide has never been clinically applied in the field of organ transplantation. A new Leflunomide derivative, FK778 and FK779, that has a shorter half-life than its mother drug were developed to resolve such problem. In this study, we have examined immunosuppressive effect, pharmacokinetics and side-effects of FK778 and FK779 in rat heart transplantation and dog kidney transplantation. In addition, we assessed immunosuppressive effect of FK778 and FK779 in combination with calcineurin inhibitors, tacrolimus (TAC) and cydosporine (CsA). In both rat and dog transplantation models, FK778 and/or FK779 prolonged allograft survival Also, there was an additive or synergistic effect when given with these calcineurin inhibitors. In a dog transplantation model, a slight leukocytopenia and anemia was observed when FK778 was administered at 6 mg/kg/day ; however, no serious side-effect was noted. We further examined an immunosuppressive effect of FK779 in a hamster-to-rat heart xenotransplantation model. FK779 effectively controlled both acute vascular and acute cellular xenograft rejections and markedly prolonged xenograft survival when combined with calcineurin inhibitors (TAC/CsA) or CD40-CD154/B7-CD28 costimulation blockades. We conclude that FK778 and FK779 are powerful and useful immunosuppressant that has a potential for clinical application in organ transplantation.