Infections and the Stability of Transplantation Tolerance

感染和移植耐受的稳定性

• 批准号: 10176362
• 负责人: Maria-Luisa Alegre
• 金额: $ 158.76万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-17 至 2023-05-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176362
• 关键词: Address; Affect; Alloantigen; Allogenic; Animals; Antigens; Avidity; Cell Count; Cells; Characteristics; Clinical; Event; Exposure to; Generations; Goals; Graft Rejection; Graft Survival; Immune Tolerance; Immunosuppression; Individual; Infection; Inflammatory; Life; Listeria monocytogenes; Longterm Follow-up; Memory; Microsurgery; Modeling; Molecular; Monitor; Mus; PD-L1 blockade; Patients; Peptide/MHC Complex; Peripheral; Phenotype; Population; Pregnancy; Regulatory T-Lymphocyte; Resistance; Skin Transplantation; Skin graft; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; Transplantation; Transplantation Tolerance; allograft rejection; congenic; experience; fetal; improved; mouse model; novel; patient tolerability; programs; skin allograft

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.

程序摘要 移植耐受性，一种对供体抗原的持久免疫抑制的状态 停止治疗是一种有吸引力的终身嫁接方法，没有全球 免疫抑制。耐受性患者的长期随访表明，某些患者可能会失去耐受性 经过多年的移植物稳定性，有时在感染后，引起了2种可能性：这种容忍度 诱导同样强大，但有些患者暴露于侵蚀的更多炎症事件 某些患者的耐受性状态或诱导的耐受性是可稳定的，而另一些患者则具有稳健性。 我们程序项目的第一个周期使用鼠标模型解决了第一种可能性 移植耐受性，对大多数炎症挑战具有耐药性，除了 单核细胞增生李斯特菌（LM）。重要的是，我们通过分析少数数量来跟踪同种异体T细胞 先天性TCR-TG同种异体反应性T细胞在移植前播种，或使用荧光PMHC I类和 II类的多种方法可以鉴定T细胞的内源性群体对模型抗原的反应。经过 比较（项目1）和后（项目2）LM感染耐受小鼠的同种异体T细胞，我们 程序发现i）通过多种冗余机制维持强大的移植耐受性 T细胞耐受性，包括约束同种反应性T细胞数，增加了调节性与 常规的T细胞，抑制常规的T细胞本质上，并将同种反应性T细胞群体限制为 同种抗原率低的克隆； ii）强大的耐受性是弹性的，因为它赞助 经历了依赖LM的移植物排斥的动物； iii）感染后的公差侵蚀并依赖 关于T细胞耐受性的单个机制，使PD-L1的阻断或Treg耗尽足以 耐受宿主的珍贵移植物拒绝是感染后的宿主，但没有在未感染的宿主中。在全球范围内，我们的计划有 证明移植耐受性不是一个无所不知的状态，而是可以在不同级别的 鲁棒性。这些观察结果凸显了需要精确定义和监视基础机制的需求 在每个容忍接收者中接受移植物，并制定策略以提高容忍度时 eoded。对于这种竞争性的续约，我们将解决第二种可能性，并非所有患者都能实现 诱导时强大的耐受性。在全球范围内，我们假设限制同种反应性T细胞的机制 子集可以区分幼稚宿主在感染后侵蚀的耐受性和 从敏感宿主中的亚稳态或失败的公差。项目1将重点介绍两个同种异体反应性的新功能 我们最近发现的T细胞是幼稚宿主中鲁棒移植耐受性的特征，即 细胞固有的低调和同种反应性T细胞对低自发克隆的约束项目2 研究适应性化是如何影响移植耐受性的主要障碍，会影响诱导 T特征耐受性的T细胞耐受性的个体机制。