Transplant Tolerance in Non-Human Primates

器官移植为成千上万的终末期器官衰竭患者提供了挽救生命和恢复健康的治疗方法。通过开发多种药物终身持续免疫抑制方案，已取得了突出的短期结果。尽管取得了这些成就，但仍然存在重大挑战，这些挑战损害了长期结果并限制了移植的应用。移植物过早丢失和死亡仍然是顽固的对手，这一点从无情和停滞的移植物和困扰我们患者的患者年流失率中可以看出。目前认为CNI毒性和供体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（CV）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础免疫抑制剂。第二代CD28通路抑制剂贝拉西普的批准提供了一种替代方案，解决了基于CNI的免疫抑制中固有的一些局限性，并为寻求移植耐受提供了期待已久的工具。贝拉西普可避免CNI诱导的肾毒性，与非常低的新发DSA率相关，并改善CV风险特征。不幸的是，大规模应用和改善长期效果的障碍仍然存在。正如我们在小鼠中的早期研究和鉴定共刺激阻断抗性排斥的NHP所预示的，贝拉西普的急性细胞排斥的速率和等级高于CNI。此外，感染和免疫损害相关的死亡率几乎肯定会继续下去，因为像它的前辈一样，目前形式的基于贝拉西普的免疫抑制是连续和终身的。此外，体液排斥正在成为晚期移植失败的主要原因，迫切需要适当的非人灵长类动物模型来解决B细胞同种免疫的问题。 我们的研究计划和本申请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性策略，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持核心来实现。

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.