Introduction: Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator involved in many critical physiological processes including immunity. ASP0028 is a recent developed S1P1/S1P5 selective agonist. It presented comparable efficacy to FTY720 and superior safety margins than FTY720. Here, we report on the effect of ASP0028 in combination with reduced dose of tacrolimus on kidney transplantation in nonhuman primates. Methods: Kidney transplants were performed in ABO matched and MLR mismatched cynomolgus monkeys. Twenty two animals were divided into three treatment groups i.e. tacrolimus (1.0 mg/kg) alone, ASP0028 (0.6 or 1.2 mg/kg) combined with tacrolimus. ASP0028 was administered from 2 days before surgery to the end of the study. The blood concentration of ASP0028 and tacrolimus were monitored in all transplanted monkeys. Peripheral blood lymphocyte number, lymphocyte subset and T cell subpopulation were monitored during the period of study. Results: The median survival times (MST) of renal allograft in tacrolimus monotherapy group, ASP0028 (0.6 or 1.2 mg/kg) plus tacrolimus combination therapy groups were 28, 41, and 61.5 days respectively (p = 0.036 and 0.001, compared with tacrolimus monotherapy group). Plasma concentrations of ASP0028 increased in a dose-related manner. The number of peripheral lymphocytes was obviously decreased immediately after the first dosing of ASP0028 in all recipient monkeys in the combination therapy groups. The number of T cells, T helper cells, suppressor/killer, effector memory, central memory, naÏve, regulatory T cells, or B cells was all decreased in recipients treated with ASP0028 and tacrolimus. In particular, CD4+, CD8+ central memory and naÏve T cells were almost perfectly reduced. No serious side effect was noted during the study. Conclusion: ASP0028 in combination with reduced-dose of tacrolimus prolongs renal allograft median survival time in nonhuman primates. ASP0028 is a promising candidate for calcineurin-inhibitor sparing regimens.
To cite this abstract in AMA style:Song L, Ma A, Dun H, Hu Y, Zeng L, Bai J, Zhang G, Koide K, Okada Y, Hanaoka K, Otsuka Y, Yamamoto R, Hirose J, Morokata T, Harada H, Seki N, Daloze P, Chen H. Effect of ASP0028 in Combination with Tacrolimus on Kidney Transplantation in Cynomolgus Monkeys, The [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/effect-of-asp0028-in-combination-with-tacrolimus-on-kidney-transplantation-in-cynomolgus-monkeys-the/. Accessed April 2, 2020.
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