EVALUATION OF CYCLOSPORINE, MYCOPHENOLATE MOFETIL, AND BREQUINAR SODIUM COMBINATION THERAPY ON HAMSTER-TO-RAT CARDIAC XENOTRANSPLANTATION

We examined the effect of CsA, mycophenolate mofetil (MM), and Brequinar sodium (BQR) combination therapy on hamster-to-rat cardiac xenotransplantation survival. Since the mechanism of rejection in concordant cardiac xenotransplantation may be antibody mediated as well as cellularly (CD4) mediated, we also examined the effect of these agents on antidonor antibody levels. In untreated controls, rejection occurred within 4 days, with elevation of cytotoxic antibody titers and severe humoral destruction of the xenografted hearts. It involved both IgM and IgG antibody-mediated humoral immunity. CsA alone (20 mg/kg/day) could not modify this pattern of rejection. High-dose MM (40/20 mg/kg/day) + BQR (12/6 mg/kg 3 times a week) combination therapy achieved slight prolongation of survival and suppressed the elevation of cytotoxic antibody titers relative to controls. While these grafts were rejected within 2 weeks, humoral destruction in the rejected xenografts and antibody deposition were reduced. Combination of CsA (20 mg/kg/day) with BQR (3 or 12 ng 3 times/week) dramatically increased graft survival. When CsA (20 mg/kg/day) was combined with MM (20 mg/kg/day) and BQR (3 mg/kg/day), xenograft survival was significantly prolonged (P<0.002); however, significant toxicity was observed. Cytotoxic antibody formation was delayed for 1 month in most cases. Histological examination revealed cellular rejection with little evidence of humoral rejection. Thus, combination therapy consisting of CsA and BQR or CsA, MM, and BQR was effective in delaying the rejection of hamster-to-LEW rat concordant cardiac xenografts. The mechanism of prolonged graft survival may involve delayed humoral response and prevention of the cellular response.