Transplant Tolerance in Non-Human Primates

移植为成千上万的人提供了挽救生命和恢复健康的治疗方法。 患有晚期器官衰竭的患者。通过以下方式取得了突出的短期成果： 多药物终身连续免疫抑制方案的开发。尽管取得了这些成就， 仍然存在着重大挑战，这些挑战损害了长期结果并限制了移植的应用。 过早的移植物丢失和死亡仍然是顽固的对手，这一点可以从无情和停滞的 移植物和病人的年流失率困扰着我们的病人。直到最近，几乎所有的移植方案 依赖钙调神经磷酸酶抑制剂作为其基础免疫抑制剂。贝拉西普的批准， 第二代CD28通路抑制剂提供了一种解决某些局限性的替代方案 这是CNI免疫抑制中固有的，并为寻求移植提供了期待已久的工具 宽容贝拉西普可避免CNI诱导的肾毒性，与非常低的新生DSA率相关， 改善CV风险状况。不幸的是，大规模应用和改善长期效果的障碍 坚持。正如我们早期在小鼠和NHP中的研究所预示的， 在急性细胞排斥反应中，贝拉西普的急性细胞排斥反应的比率和等级高于CNI。重要的是我们 最近发现了一种记忆T细胞生物标志物，与共刺激风险增加相关 阻断性排斥反应（CoBRR）在NHP和人类。使用这种预测性生物标志物可以允许 我们确定最佳候选人共刺激阻断为基础的耐受诱导疗法。此外，本发明还 探索共刺激非依赖性记忆T细胞利用的关键途径， 下一代细胞疗法，包括优化的eTreg、骨髓产品和间充质干细胞 基质细胞（MSCs）将提供强有力的策略，以减轻排斥反应的风险和促进耐受性 在排斥风险高的受者中进行诱导。耐受诱导方案的发展 基于个体接受者的免疫状态， 诱导，以最大限度地减少围移植免疫抑制和保护性免疫。因此，中央 我们的研究计划和本申请的目标是开发临床适用的方法，以解决 近期需求，并最终开发出广泛适用的耐受性策略，用于临床 移植，与潜在的主题，同样的策略可能不是最佳的每一个收件人。这 这一目标将通过两个相互关联的项目和一个支持性的科学核心来实现。

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.