Transplant Tolerance in Non-Human Primates

移植为数十万患有终末期器官衰竭的患者提供了挽救生命和恢复健康的希望。通过开发多种药物的终生持续免疫抑制方案，取得了显著的短期效果。尽管取得了这些成就，但仍存在严重的挑战，这些挑战危及长期结果，限制了移植的应用。移植物过早丢失和死亡仍然是顽固的对手，困扰我们患者的移植物不可阻挡和停滞不前的移植物和患者的年度流失率就是明证。目前的观点认为，CNI毒性和供者特异性抗体是肾移植失败的主要驱动因素，而过早死亡的主要原因是心血管疾病、感染和恶性肿瘤。直到最近，几乎所有的移植方案都依赖于钙调神经磷酸酶抑制剂作为其基石免疫抑制剂。第二代CD28途径抑制剂belatacept的批准提供了一种替代方案，它解决了基于CNI的免疫抑制的一些固有限制，并在寻求移植耐受方面提供了一个期待已久的工具。贝拉西普可避免CNI诱导的肾毒性，与非常低的从头DSA率相关，并改善心血管风险状况。不幸的是，大规模应用和改善长期结果的障碍依然存在。正如我们在小鼠和NHP中识别共刺激阻断抵抗排斥反应的早期研究所预示的那样，Ballatacept组的急性细胞排斥反应的发生率和分级高于CNI组。此外，感染和免疫损害相关的死亡几乎肯定会继续下去，因为像它的前身一样，目前形式的基于贝拉坦的免疫抑制是持续的和终身的。此外，体液排斥正在成为晚期移植失败的主要原因，迫切需要足够的非人类灵长类动物模型来解决B细胞同种免疫的问题。 我们研究计划和这项应用的中心目标是开发临床适用的方法，以满足近期需求，并最终开发广泛适用的耐受策略，用于临床移植。这一目标将通过四个相互关联的项目和两个支助核心来实现。

Transplantation offers the promise of life saving and health restoring therapy for hundreds of thousands of patients suffering from end-stage organ failure. Outstanding short-term outcomes have been achieved through the development of multi-drug life-long continuous immunosuppressive regimens. Despite these achievements, significant challenges remain that compromise the long-term outcomes and limit the application of transplantation. Premature graft loss and death remain as stubborn adversaries as evidenced by the inexorable and stagnant graft and patient annual attrition rates that plague our patients. Current thinking holds that CNI-toxicity and donor-specific antibodies are predominant drivers of kidney graft failure, whereas the principle causes of premature death are cardiovascular (CV) disease, infection, and malignancy. Until recently, virtually all transplant regimens relied on calcineurin-inhibitors as their cornerstone immunosuppressive agent. The approval of belatacept, a second generation CD28 pathway inhibitor, provides an alternative which addresses some of the limitations inherent in CNI-based immunosuppression and provides a long-awaited tool in the quest for transplantation tolerance. Belatacept avoids CNI-induced nephrotoxicity, is associated with very low de novo DSA rates, and improves the CV risk profile. Unfortunately, barriers to wide-scale application and improving long-term results persist. As foreshadowed by our early studies in mice and NHP identifying costimulation blockade-resistant rejection, the rates and grades of acute cellular rejection are higher with belatacept than CNI. In addition, infection and immune compromise-related mortality will almost certainly continue because like its predecessors, belatacept-based immunosuppression in its current form is continuous and life-long. Furthermore, humoral rejection is emerging as a major cause of late-graft failure, and adequate non-human primate models to address the problem of B cell alloimmunity are urgently needed. The central goal of our research program and this application is to develop clinically applicable approaches to address near-term needs and ultimately to develop broadly applicable tolerance strategies for use in clinical transplantation. This goal will be accomplished via four interrelated projects and two supporting cores.