Efficacy of Single-Agent Immunosuppressive Regimens in a Murine Model of Vascularized Composite Allotransplantation.

Guo, Yinan; Messner, Franka; Etra, Joanna W; Beck, Sarah E; Kalsi, Richa; Furtmüller, Georg J; Schneeberger, Stefan; Oh, Byoung Chol; Brandacher, Gerald

BACKGROUND We herein investigate the safety and efficacy of single-agent anti-rejection regimens in a mouse vascularized composite allotransplantation (VCA) model. METHODS Orthotopic hind-limb transplantations (Balb/c→C57BL/6) were performed using 6-8 week old mice. A thirty-day regimen of either rapamycin, tacrolimus (both 1, 3, 5mg/kg/d) or cyclosporine (25, 35, 50mg/kg/d) was used. Primary endpoints were animal and graft survival, and secondary chimerism and regulatory T cell levels. RESULTS For rapamycin and tacrolimus given at 1, 3, and 5mg/kg/day, median graft survival time (MST) was 23d(18-28d), 30d(23-30d), and 30d(30-30d) and 14d(13-18d), 30d(16-30d), and 30d(30-30d) respectively. For cyclosporine dosed at 25 and 35mg/kg/day, MST was 15d(12-18d) and 21d(14-27d). Toxicity from CsA 50mg/kg led to 100% mortality. Mixed chimerism levels were higher in rapamycin treated animals than in tacrolimus treated recipients (p=0.029). Tacrolimus was superior in preventing leukocyte recruitment to the allograft. CONCLUSIONS In murine VCA, no standardized immunosuppressive regimen exists, limiting comparability of outcomes and survival. Our data demonstrate that rapamycin and tacrolimus maintenance treatment at 5mg/kg/d both yielded allograft survival (< grade 3 rejection) in all animals. Rapamycin displayed less toxicity and maintained mixed chimerism, but was not as potent in controlling leukocyte recruitment compared to tacrolimus.