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

Objective: The macrolide immunosuppressant RAD and the immunomodulator FTY7 20 have distinct mechanisms of action. We investigated the efficacy of RAID (everolimus, certican (R)) alone or in combination with FTY720 on graft su rvival (GS) and histology in comparison with CsA, using mouse strains with strong MHC disparity. Methods: Heterotopic cardiac grafting was performed u sing the C57B1/6 to C3H strain combination. Osmotic mini-pumps filled with CsA or RAD were implanted subcutaneously. FTY720 was administered as a sing le daily dose by gavage. Peripheral lymphocyte count (PLC) was determined a t 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 f indings: 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 RAID resulted in 10. 5, 20, > 56 and > 56 days MST, respectively. FTY720 lowered the PLC signifi cantly, 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 si gnificantly the perivascular infiltration and endothelialitis in the grafts compared with RAID monotherapy. Conclusions: Under the conditions of the p resent experiment RAD was more potent than CsA in extending the GS. Combini ng FTY720 and RAD was well tolerated with respect to weight gain and lack o f clinically detectable infections in the mice. The 2-drug regimens suppres sed the inflammatory allo-response better than RAD monotherapy. (C) 2001 El sevier Science B.V. All rights reserved.