Selective decrease of donor-reactive T_regs after liver transplantation limits T_reg therapy for promoting allograft tolerance in humans

Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (T_regs) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen–reactive T_reg (darT_reg) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darT_reg infusion, 5 received darT_regs, and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 10⁶ cells. darT_reg infusion was not associated with adverse events. Two darT_reg-infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darT_regs. Mechanistic studies revealed generalized T_reg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of T_reg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.