Comparative Study of Human and Cynomolgus T-cell Depletion With rabbit anti-thymocyte globulin (rATG) treatment - for dose adjustment in a non-human primate transplantation model

Abstract

Rabbit-antithymocyte globulin (rATG) is commonly used in solid organ transplantation to prevent and treat allograft rejection. Although rATG is also commonly used in non-human primates, the optimal dose has not been reported. In this study, we evaluated which cumulative dose of rATG was most appropriate for transplantation in a non-human primate (NHP). Cynomolgus monkeys were treated with 5 mg/kg of rATG (Thymoglobulin®, Genzyme Ltd., UK) intravenously twice on day 0 and 2 (a total of 10 mg/kg, n = 2) or 4 times on day 0, 1, 2 and 3 (a total of 20 mg/kg, n = 6). And, we performed an allo-kidney transplantation (KT) in cynomolgus monkeys (n = 4) with a cumulatively 20 mg/kg of rATG induction. Also, their subpopulation of T cells like naïve, central memory and effector memory T cells were compared in the kinetics of human KT patients (n = 7). The kinetics of lymphocytes decreased rapidly at day 1 and then was maintained for 2 weeks in the 20 mg/kg rATG group, while maintenance was not observed in the 10 mg/kg rATG group. During the early period of rATG treatment in NHP KT model, their T cell subpopulation in the 20 mg/kg group showed a similar pattern of change to kidney transplant patients treated with rATG (1.5 mg/kg, 3 days). However, the pattern of B cells was different from those of human KT patients. These data indicate that the lymphocyte-depletion induced by rATG was influenced by the cumulative dose, and that an rATG dose of 20 mg/kg is suitable for induction therapy in renal transplantation in cynomolgus monkeys when compared to human KT.