Transplant Tolerance in Non-Human Primates

移植为数十万人提供了挽救生命和恢复健康的希望 患有终末期器官衰竭的患者。通过以下途径取得了突出的短期成果 多药终生持续免疫抑制方案的开发。尽管取得了这些成就， 严重的挑战仍然存在，影响长期结果并限制移植的应用。 过早的移植物丢失和死亡仍然是顽固的对手，无情和停滞不前的 移植物和患者每年的流失率，困扰着我们的患者。直到最近，几乎所有的移植方案 依靠钙调神经磷酸酶抑制剂作为其基石免疫抑制剂。拉帕西普的批准，一个 第二代CD28途径抑制剂提供了一种替代方案，解决了一些限制 这是CNI免疫抑制所固有的，为寻求移植提供了一个期待已久的工具 宽容。贝拉西普可避免CNI诱导的肾毒性，与非常低的从头DSA率有关，以及 改善简历风险状况。不幸的是，大规模应用和提高长期效果的障碍 坚持不懈。正如我们在小鼠和NHP上的早期研究所预示的那样，识别共刺激阻断抵抗 排斥反应、急性细胞排斥反应发生率和急性细胞排斥反应分级均高于CNI组。重要的是，我们 最近发现了一种记忆T细胞生物标记物，它与共刺激增加的风险有关 NHP和人类的抗封锁排斥反应(CoBRR)。使用这种预测性生物标记物可以 美国确定共刺激-基于阻断的耐受诱导疗法的最佳候选者。此外， 共刺激非依赖性记忆T细胞利用的关键途径的探索和发展 新一代细胞疗法，包括优化的eTreg、骨髓产品和间充质 基质细胞(MSCs)将提供强大的策略来降低排斥风险和促进耐受性 对排斥风险较高的受者进行诱导。耐受诱导方案的研究进展 基于个体接受者的免疫状态将有助于个性化的耐受策略 诱导，以最大限度地减少移植围术期的免疫抑制，并保持保护性免疫。因此，中央 我们的研究计划和这项应用的目标是开发临床适用的方法来解决 近期需求，并最终开发广泛适用的耐受策略，用于临床 移植，其基本主题是，同样的战略不一定对每个接受者都是最佳的。这 这一目标将通过两个相互关联的项目和一个辅助科学核心来实现。

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 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. 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 that 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. Importantly, we have recently identified a memory T cell biomarker that correlated with increased risk of costimulation blockade-resistant rejection (CoBRR) in both NHP and humans. The use of this predictive biomarker may allow us to identify optimal candidates for costimulation-blockade-based tolerance induction therapies. Further, exploration of critical pathways utilized by costimulation-independent memory T cells, and development of next-generation cellular therapies including optimized eTreg, bone marrow products, and mesenchymal stromal cells (MSCs) will provide powerful strategies to mitigate risk of rejection and promote tolerance induction in recipients in which the risk of rejection is high. The development of tolerance induction protocols based on the immune status of individual recipients will facilitate personalized strategies for tolerance induction, to minimize peri-transplant immunosuppression and preserve protective immunity. Thus, 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, with the underlying theme that the same strategy may not be optimal for every recipient. This goal will be accomplished via two interrelated projects and a supporting scientific core.