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.

计划概要 移植耐受，指移植后对供体抗原长期无反应的一种状态。 停止治疗是终身移植接受的一种有吸引力的方法，无需全球性的 免疫抑制。对耐受患者的长期随访表明，某些患者可能会丧失耐受性 个体在移植物稳定多年后，有时在感染后，提出了两种可能性： 诱导同样有效，但一些患者暴露于更多的炎症事件，从而侵蚀了 耐受状态，或者诱导时的耐受性在某些患者中是亚稳定的，而在其他患者中是强的。 我们的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 移植耐受性强，可抵抗大多数炎症挑战，但以下情况除外 单核细胞增生李斯特氏菌 (Lm)。重要的是，我们通过分析少量的同种异体反应性 T 细胞来追踪 移植前接种同源 TCR-Tg 同种反应性 T 细胞，或使用荧光 pMHC I 类和 II 类多聚体，用于识别对模型供体抗原有反应的内源性 T 细胞群。经过 比较耐受小鼠 Lm 感染之前（项目 1）和之后（项目 2）的同种反应性 T 细胞，我们 程序发现 i) 强大的移植耐受性是由多个冗余机制维持的 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 传统 T 细胞，从本质上抑制传统 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和力的克隆； ii) 稳健的耐受性是有弹性的，因为它会自发地返回 经历过 Lm 依赖性移植物排斥反应的动物； iii) 感染后的耐受性被侵蚀和依赖 T 细胞耐受的单一机制，例如阻断 PD-L1 或耗竭 Tregs 就足以 在感染后耐受的宿主中会引起移植排斥，但在未感染的宿主中则不会。在全球范围内，我们的计划已 证明移植耐受不是一种全有或全无的状态，而是可以存在于不同水平 鲁棒性。这些观察结果凸显了精确定义和监测潜在机制的必要性 每个耐受接受者的移植物接受情况，并制定策略以提高耐受性 侵蚀。对于本次竞争性续保，我们将解决第二种可能性，即并非所有患者都能实现 诱导时具有强大的耐受性。在全球范围内，我们假设抑制同种反应性 T 细胞的机制 子集可以区分在幼稚宿主中建立的稳健耐受性和感染后受损的耐受性，并且 来自致敏宿主的亚稳态或耐受失败。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 研究异体敏化（诱导移植耐受的主要障碍）如何影响诱导 具有鲁棒耐受性特征的 T 细胞耐受的个体机制。