Combination effect of mycophenolate mofetil with mizoribine on cell proliferation assays and in a mouse heart transplantation model

Abstract

Background: Mycophenolate mofetil (MMF) is a highly potent immunosuppressant that suppresses the proliferation of T and B cells by the uncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH). Consequently, under MMF immunosuppression, good graft survival has been achieved in clinical organ transplantation, although MMF shows adverse gastrointestinal effects. Mizoribine (MZ) also inhibits IMPDH in a competitive manner and is used clinically for organ transplantation in Japan as an immunosuppressant with fewer adverse gastrointestinal effects. Therefore, in this study we investigated the synergistic effects on in vitro and in vivo assays of mice of a combination of MMF with MZ immunosuppression.

Methods: Mixed lymphocyte reaction (MLR) assay and a mouse heart transplantation model were used to evaluate the immunosuppressive effect of MMF with MZ. The median-effect principle and a combination index (CI) were employed to determine synergism, an additive effect, or antagonism.

Results: Combination of MMF with MZ resulted in mild synergistic effects in the inhibition of MLR (CI = 0.854-1.143). In the mouse heart transplantation model, C57BL/6 recipients who received a BALB/c heart under the combination of MMF and MZ at 40 + 40 or 80 + 80 mg/kg/day showed a strong synergistic prolongation of graft survival with 19.7 +/- 18.9 (P = 0.0012, CI = 0.438) and 78.4 +/- 36.9 days (P = 0.0002, CI = 0.317), respectively, compared with recipients treated with MMF or MZ monotherapy. CONCLUSIONS.: The combination of MMF and MZ showed mild synergistic effects in the inhibition of MLR and strong synergistic effects in a mouse heart transplantation model.