Combined FTY720/cyclosporine A treatment promotes graft survival and lowers the peripheral lymphocyte count in DA to Lewis heart and skin transplantation models

Objective: The immunomodulator, FTY720, lowers the peripheral lymphocyte co unt (PLC) by inducing migration of circulating lymphocytes to secondary lym phoid organs. We investigated the efficacy of mono- vs. combined-FTY720/CsA therapy on graft survival (GS) and on lowering the PLC in a solid organ an d a skin graft model, using strains with strong MHC disparity. Methods: Het erotopic cardiac or tail skin grafting was performed using the DA(RT1(a)) t o Lewis (RT1(1)) rat strain combination. FTY720 was administered as a singl e daily dose by gavage alone or in combination with subcutaneously delivere d CsA. PLC, body weight and drug concentrations were determined on day 7, 2 8, or the day of rejection. Main findings: In placebo-treated animals the h eart and skin allografts rejected after 6 and 8 days. FTY720 delayed reject ion of both the solid organ and skin grafts. The maximal effect was achieve d at 1 mg kg(-1) day(-1) FTY720, resulting in a median survival time (MST) of 14 days for both allotransplants comparable to the effect achieved by 1 mg kg(-1) day(-1) CsA in both models. In the cardiac graft experiment with CsA co-administration, doses of 0.3 and 1 mg/kg were used. Under these cond itions very small doses of FTY720 were effective in maintaining grafts thro ughout the treatment period. Adding higher FTY720 doses to the 1 mg kg(-1) day(-1) CsA was needed to effectively extend the skin GS, e.g. 0.3 mg kg(-1 ) day(-1) FTY720 prolonged GS from 13 to 47.5 days MST, i.e. well beyond th e 28 day-treatment period. CsA did not influence the PLC at clinically rele vant doses. FTY720 lowered the PLC significantly and dose-dependently, at d oses lower than those needed for the prolongation of both cardiac and skin GS with FTY720 monotherapy. In rats with skin grafts the PLC was markedly l owered up to 1 mg kg(-1) day(-1) FTY720, whereas, in the heart model, it wa s lowered up to 0.1 mg kg(-1) day(-1). Independently of the graft type, wit hin the combination regimens 0.3 mg kg(-1) day(-1) FTY720 achieved a maxima l PLC depletion. Conclusions: Combining FTY720 and CsA was very well tolera ted with respect to weight gain and lack of any clinically detectable infec tions. In the strain combination used FTY720 monotherapy was less effective than previously reported in maintaining grafts. The two-drug regimens exte nded strikingly the GS for both models. However, the prolongation of the he art GS was smoothly dose-related with FTY720 doses ranging from 0.01 to 1 m g kg(-1) day(-1), whereas, the skin graft prolongation was modest at doses up to 0.1 mg kg(-1) day(-1) and remarkably enhanced at 0.3 and 1 mg kg(-1) day(-1) FTY720. (C) 2001 Elsevier Science B,V. All rights reserved.