Infections and the Stability of Transplantation Tolerance

节目概要 移植耐受是一种在移植后对供体抗原长期免疫无反应的状态。 停止治疗是一种有吸引力的终身移植物接受方法， 免疫抑制对耐受患者的长期随访显示，在某些情况下， 个体在移植物稳定多年后，有时在感染后，提出了2种可能性： 诱导同样稳健，但一些患者暴露于更多的炎症事件， 耐受状态，或诱导时耐受在一些患者中是亚稳定的，而在另一些患者中是稳定的。 我们计划项目的第一个周期使用小鼠模型解决了第一种可能性， 移植耐受性是强大的，对大多数炎性挑战有抵抗力，除了 单核细胞增生李斯特菌（Lm）。重要的是，我们通过分析少量的同种异体反应性T细胞， 同种异体TCR-Tg同种异体反应性T细胞，在移植前接种，或使用荧光pMHC I类， II类多聚体，以鉴定对模型供体抗原有反应性的内源性T细胞群体。通过 比较耐受小鼠Lm感染前（项目1）和后（项目2）的同种异体反应性T细胞， 该计划发现i）强大的移植耐受性是由多种冗余机制维持的， T细胞耐受性，包括限制同种异体反应性T细胞数量，增加调节性T细胞与非调节性T细胞的比例， 常规T细胞，内在地抑制常规T细胞并抑制同种异体反应性T细胞群， 对同种异体抗原具有低亲合力的克隆; ii）稳健的耐受性是有弹性的，因为它自发地返回同种异体抗原。 经历了Lm依赖性移植排斥的动物; iii）感染后的耐受性被侵蚀并依赖于 对T细胞耐受性的单一机制，例如PD-L1的阻断或T细胞的耗竭足以 在感染后的耐受宿主中加速移植物排斥，但在未感染的宿主中不加速。在全球范围内，我们的计划 表明移植耐受不是一个全有或全无的状态，而是可以存在于不同的水平， 鲁棒性这些意见突出表明，需要准确界定和监测其背后的机制， 在每个耐受受体的移植接受性，并制定策略，以提高耐受性时，它成为 被侵蚀了对于本次竞争性续约，我们将解决第二种可能性，即并非所有患者都能实现 诱导时耐受性强。在全球范围内，我们假设抑制同种异体反应性T细胞的机制 亚群可以区分幼稚宿主中建立的稳健耐受性与感染后侵蚀的耐受性， 致敏宿主中的亚稳态或失效耐受性。项目1将重点关注同种异体反应的2个新特征 我们最近发现，T细胞在幼稚宿主中具有强大的移植耐受性，即， 细胞固有的低反应性和同种异体反应性T细胞对低亲合力克隆的限制项目2将 研究同种异体致敏，诱导移植耐受的主要障碍，如何影响诱导 T细胞耐受性的个体机制，其特征在于稳健的耐受性。

PROGRAM SUMMARY Transplantation tolerance, a state of long-lasting immune unresponsiveness to donor antigens after cessation of therapy, is an attractive approach for life-long graft acceptance without global immunosuppression. Long-term follow up of tolerant patients has revealed that tolerance can be lost in some individuals after years of graft stability, sometimes after infections, raising 2 possibilities: that tolerance at induction was equally robust but some patients were exposed to more inflammatory events that eroded the state of tolerance, or that tolerance at induction was metastable in some patients and robust in others. The first cycle of our Program Project addressed the first possibility using a mouse model of transplantation tolerance that is robust and resistant to most inflammatory challenges with the exception of Listeria monocytogenes (Lm). Importantly, we tracked alloreactive T cells by analyzing small numbers of congenic TCR-Tg alloreactive T cells seeded before transplantation, or using fluorescent pMHC Class I and Class II multimers to identify endogenous populations of T cells reactive to model donor antigens. By comparing alloreactive T cells before (Project 1) and after (Project 2) Lm infection of tolerant mice, our Program discovered that i) robust transplantation tolerance is maintained by multiple redundant mechanisms of T cell tolerance, including constraining alloreactive T cell numbers, increasing the ratio of regulatory to conventional T cells, inhibiting conventional T cells intrinsically and restraining alloreactive T cell populations to clones with low avidity for alloantigen; ii) robust tolerance is resilient because it spontaneously returned in animals that experienced Lm-dependent graft rejection; iii) tolerance after infection is eroded and dependent on single mechanisms of T cell tolerance such that blockade of PD-L1 or depletion of Tregs was sufficient to precipitate graft rejection in tolerant hosts post-infection but not in uninfected hosts. Globally, our Program has demonstrated that transplantation tolerance is not an all-or-none state, but rather can exist at different levels of robustness. These observations highlight the need to precisely define and monitor the mechanisms underlying graft acceptance in each tolerant recipient and to devise strategies to improve tolerance when it becomes eroded. For this Competitive Renewal, we will address the second possibility, that not all patients achieve robust tolerance at induction. Globally, we hypothesize that the mechanisms restraining alloreactive T cell subsets can distinguish robust tolerance established in naive hosts from eroded tolerance after infection, and from metastable or failed tolerance in sensitized hosts. Project 1 will focus on 2 novel features of alloreactive T cells that we recently discovered as characteristic of robust transplantation tolerance in naïve hosts, namely, cell intrinsic hyporesponsiveness and the constraint of alloreactive T cells to low avidity clones Project 2 will study how allosensitization, a major barrier to the induction of transplantation tolerance, affects the induction of the individual mechanisms of T cell tolerance that characterize robust tolerance.