A critical question facing the field of transplantation is how to control effector T cell (T_eff) activation while preserving regulatory T cell (T_reg) function. Standard calcineurin inhibitor–based strategies can partially control T_effs, but breakthrough activation still occurs, and these agents are antagonistic to T_reg function. Conversely, mechanistic target of rapamycin (mTOR) inhibition with sirolimus is more T_reg-compatible but is inadequate to fully control T_eff activation. In contrast, blockade of OX40L signaling has the capacity to partially control T_eff activation despite maintaining T_reg function. We used the nonhuman primate graft-versus-host disease (GVHD) model to probe the efficacy of combinatorial immunomodulation with sirolimus and the OX40L-blocking antibody KY1005. Our results demonstrate significant biologic activity of KY1005 alone (prolonging median GVHD-free survival from 8 to 19.5 days), as well as marked, synergistic control of GVHD with KY1005 + sirolimus (median survival time, >100 days; P < 0.01 compared to all other regimens), which was associated with potent control of both T_H/T_C1 (T helper cell 1/cytotoxic T cell 1) and T_H/T_C17 activation. Combined administration also maintained T_reg reconstitution [resulting in an enhanced T_reg/T_eff ratio (40% over baseline) in the KY1005/sirolimus cohort compared to a 2.9-fold decrease in the unprophylaxed GVHD cohort]. This unique immunologic signature resulted in transplant recipients that were able to control GVHD for the length of analysis and to down-regulate donor/recipient alloreactivity despite maintaining anti–third-party responses. These data indicate that combined OX40L blockade and sirolimus represents a promising strategy to induce immune balance after transplant and is an important candidate regimen for clinical translation.

移植领域面临的一个关键问题是如何在保持调节性T细胞（T _reg）功能的同时控制效应T细胞（T _eff）的激活。基于钙调神经磷酸酶抑制剂的标准策略可以部分控制T _effs，但仍会出现突破性激活，并且这些试剂均对抗T _reg功能。相反地，雷帕霉素（mTOR的）抑制与西罗莫司的机械目标是多个T _REG兼容但不足以完全控制Ť _EFF活化。相反，尽管维持T _reg，但是OX40L信号传导的阻断具有部分控制T _eff活化的能力。功能。我们使用非人类灵长类动物移植物抗宿主病（GVHD）模型来探讨西罗莫司和OX40L阻断抗体KY1005的组合免疫调节的功效。我们的结果表明，单独使用KY1005具有显着的生物学活性（将无GVHD的中位生存期从8天延长至19.5天），以及KY1005 +西罗莫司对GVHD的显着协同控制（中位生存时间> 100天；与<相比，P <0.01所有其他方案），与有效控制T _H / T _C 1（T辅助细胞1 /细胞毒性T细胞1）和T _H / T _C 17激活有关。联合给药还维持了T _reg的重构[导致增强的T _reg/ T _eff比（比基线高40％）在KY1005 /西罗莫司（Sirolimus）人群中，相比之下，未预防的GVHD人群降低2.9倍]。这种独特的免疫学特征使移植受者能够控制GVHD的分析时间，并且尽管维持了抗第三方的反应，却能够下调供体/受体的同种异体反应性。这些数据表明，OX40L阻断剂和西罗莫司的结合代表了移植后诱导免疫平衡的有前途的策略，并且是临床翻译的重要候选方案。