Efficacy of SDZ RAD compared with CsA monotherapy and combined RAD/FTY720 treatment in a murine cardiac allotransplantation model

Abstract Objective: The macrolide immunosuppressant RAD and the immunomodulator FTY720 have distinct mechanisms of action. We investigated the efficacy of RAD (everolimus, certican®) alone or in combination with FTY720 on graft survival (GS) and histology in comparison with CsA, using mouse strains with strong MHC disparity. Methods: Heterotopic cardiac grafting was performed using the C57Bl/6 to C3H strain combination. Osmotic mini-pumps filled with CsA or RAD were implanted subcutaneously. FTY720 was administered as a single daily dose by gavage. Peripheral lymphocyte count (PLC) was determined at 1, 4 and 8 weeks or on the day of sacrifice. Body weight was recorded on the day of surgery and weekly. Grafts were histologically evaluated. Main findings: In placebo-treated mice the allografts were rejected after 7 days. Monotherapy with 10 and 30 mg/kg/day CsA achieved 10 and 22.5 days median survival time (MST), while 0.1, 0.3, 1 and 3 mg/kg/day RAD resulted in 10.5, 20, >56 and >56 days MST, respectively. FTY720 lowered the PLC significantly, while the lower CsA dose and RAD did not influence the PLC. Adding FTY720 to the 0.6 mg/kg/day dose of RAD extended GS modestly but reduced significantly the perivascular infiltration and endothelialitis in the grafts compared with RAD monotherapy. Conclusions: Under the conditions of the present experiment RAD was more potent than CsA in extending the GS. Combining FTY720 and RAD was well tolerated with respect to weight gain and lack of clinically detectable infections in the mice. The 2-drug regimens suppressed the inflammatory allo-response better than RAD monotherapy.