Emory Transplant Center, Emory University, Atlanta, GA, USA.
Am J Transplant. 2012 Sep;12(9):2395-405. doi: 10.1111/j.1600-6143.2012.04074.x. Epub 2012 Jul 9.
Chronic allograft rejection is a major impediment to long-term transplant success. Humoral immune responses to alloantigens are a growing clinical problem in transplantation, with mounting evidence associating alloantibodies with the development of chronic rejection. Nearly a third of transplant recipients develop de novo antibodies, for which no established therapies are effective at preventing or eliminating, highlighting the need for a nonhuman primate model of antibody-mediated rejection. In this report, we demonstrate that depletion using anti-CD3 immunotoxin (IT) combined with maintenance immunosuppression that included tacrolimus with or without alefacept reliably prolonged renal allograft survival in rhesus monkeys. In these animals, a preferential skewing toward CD4 repopulation and proliferation was observed, particularly with the addition of alefacept. Furthermore, alefacept-treated animals demonstrated increased alloantibody production (100%) and morphologic features of antibody-mediated injury. In vitro, alefacept was found to enhance CD4 effector memory T cell proliferation. In conclusion, alefacept administration after depletion and with tacrolimus promotes a CD4+memory T cell and alloantibody response, with morphologic changes reflecting antibody-mediated allograft injury. Early and consistent de novo alloantibody production with associated histological changes makes this nonhuman primate model an attractive candidate for evaluating targeted therapeutics.
慢性移植排斥反应是长期移植成功的主要障碍。同种异体抗原的体液免疫反应是移植中日益严重的临床问题，越来越多的证据表明同种抗体与慢性排斥反应的发展有关。近三分之一的移植受者会产生新的抗体，目前尚无有效的治疗方法可以预防或消除这些抗体，这突出表明需要建立一个灵长类动物抗体介导排斥反应模型。在本报告中，我们证明，使用抗-CD3 免疫毒素（IT）进行耗竭，结合包括他克莫司和/或阿来昔单抗的维持性免疫抑制，可可靠地延长恒河猴的肾移植存活时间。在这些动物中，观察到 CD4 细胞的再增殖和增殖出现了偏向性，尤其是添加阿来昔单抗时。此外，阿来昔单抗治疗的动物表现出更高的同种抗体产生（100%）和抗体介导损伤的形态特征。体外实验发现，阿来昔单抗增强了 CD4 效应记忆 T 细胞的增殖。总之，在耗竭后使用他克莫司和阿来昔单抗进行治疗可促进 CD4+记忆 T 细胞和同种抗体反应，形态学变化反映了抗体介导的移植物损伤。早期且一致的新产生的同种抗体，并伴有相关的组织学变化，使这种灵长类动物模型成为评估靶向治疗的有吸引力的候选模型。
