Emory Transplant Center.
Yerkes National Primate Research Center, Atlanta, Georgia, USA.
JCI Insight. 2017 Mar 9;2(5):e90317. doi: 10.1172/jci.insight.90317.
The potential of costimulation blockade to serve as a novel transplant immunosuppression strategy has been explored for over 20 years, culminating in the recent clinical approval of belatacept for renal transplant patients. Despite improving long-term graft function and survival compared with calcineurin inhibitors, clinical acceptance of belatacept has been hindered by elevated rates of acute rejection. We examined the signaling pathways required to activate costimulation blockade-resistant alloreactive T cells and identified the OX40/OX40L secondary costimulatory pathway as a promising target. We next sought to improve the clinical efficacy of traditional costimulation blockade using belatacept by coupling it with anti-OX40L. Using a murine transplant model, we demonstrate that combined blockade enhances the suppression of alloreactive T cell proliferation and effector functions including both cytokine release and cytotoxic degranulation. We also show that anti-OX40L may be particularly useful in targeting alloreactive memory T cell responses that are relatively unaffected by traditional costimulation blockade regimens. Finally, we translated this therapy to a clinically relevant nonhuman primate renal transplant model, validating the efficacy of this regimen in a potentially novel steroid- and calcineurin inhibitor-free immunosuppression regimen.
阻断共刺激作为一种新型移植免疫抑制策略的潜力已经被探索了超过 20 年，最终导致了 belatacept 最近被批准用于肾移植患者。尽管与钙调磷酸酶抑制剂相比，它提高了长期移植物功能和存活率，但 belatacept 的临床应用受到急性排斥反应发生率升高的阻碍。我们研究了激活共刺激阻断耐药同种反应性 T 细胞所需的信号通路，并确定 OX40/OX40L 二级共刺激途径是一个有前途的靶点。接下来，我们试图通过与抗 OX40L 结合来提高 belatacept 的传统共刺激阻断的临床疗效。我们使用小鼠移植模型证明，联合阻断增强了对同种反应性 T 细胞增殖和效应功能的抑制作用，包括细胞因子释放和细胞毒性脱颗粒。我们还表明，抗 OX40L 可能特别有用，因为它可以靶向传统共刺激阻断方案相对不受影响的同种反应性记忆 T 细胞反应。最后，我们将这种疗法转化为一种临床相关的非人类灵长类动物肾移植模型，验证了这种方案在一种潜在的新型无类固醇和钙调磷酸酶抑制剂免疫抑制方案中的疗效。
