Infections and the Stability of Transplantation Tolerance

总体汇总 移植耐受是一种在停止治疗后对供体抗原的低反应性状态， 有吸引力的方法，实现终身移植接受没有全面的免疫抑制。宽容是罕见的 在临床上，即使获得了，也会随着时间的推移而丢失，有时是在感染后。了解障碍 在临床上诱导移植耐受，以及持久耐受的脆弱性，是至关重要的， 实现一次移植终身的目标。在临床上诱导移植耐受的一个障碍是T 单元存储器（TMS 320 F2401）。Tcl 4与共刺激的内在独立性及其对Tcl 4的抗性 解释诱导耐受性的困难。项目2确定了一个额外的障碍， 拮抗移植耐受的诱导：少量的T细胞可以“感染”幼稚T细胞， 记忆样特征和通过“链接致敏”过程抵抗共刺激阻断（CoB）。 一旦建立，移植耐受性可能表现出其维持的脆弱性，特别是在移植期间。 促炎性感染的情况。项目1已经确定了通过以下方式实现的功能障碍状态的异质性： CoB后的多克隆同种异体反应性T细胞，对同种异体抗原特异性的T细胞迅速下调 在移植后的移植物中，T细胞对移植物抗原具有低亲和力/亲合力， 尽管CoB。这些功能性T细胞在稳定状态下不会对移植物构成威胁，因为它们受到控制 通过Tdlc。然而，已知由一些感染引起的炎性细胞因子使TGFAP不稳定，激活TGFAP， APC和上调移植物MHC，使得这些保留功能的T细胞可以介导移植物排斥。 这两个项目都确定了解决这些障碍/弱点的办法。项目2发现，暴露捐助者- 对半同种异体妊娠的反应性TclD使TclD重新编程为对CoB敏感。项目 1表明重复注射供体脾细胞可以诱导更广泛的同种异体反应性细胞库功能障碍， T细胞，包括T细胞。我们将研究获得功能障碍的分子机制 并在项目之间进行比较，从而强调项目的协同作用。的全球假说 目前提交的材料是，了解将致敏性和异质性联系在一起的机制， 同种异体反应性T细胞功能障碍阻止耐受诱导或破坏已建立的耐受，以及 暴露于妊娠或重复供体脾细胞注射克服这些缺陷的机制 障碍，将有助于确定耐受性的关键分子驱动因素，稳健耐受性与不稳定耐受性的标志物， 有助于设计新的治疗方法以诱导持久的移植耐受。项目1地址 同种异体抗原表达的持续时间决定T细胞功能障碍水平的机制， CoB（目的1），并检验低亲和力/亲合力同种异体反应性T细胞准备介导排斥反应的假设 在感染期间（目标2）。项目2调查关联致敏（目标1）背后的机制，以及 CD 8+（Aim 2）和CD 4+（Aim 3）同种异体反应性T细胞通过妊娠重新编程。

Overall Summary Transplantation tolerance, a state of hyporesponsiveness to donor antigens after cessation of therapy, is an attractive approach for achieving life-long graft acceptance without global immunosuppression. Tolerance is rare in the clinic, and even when attained can be lost over time, sometimes after infections. Understanding the barriers to the induction of transplant tolerance in the clinic, and the vulnerabilities to durable tolerance, is essential to achieving the goal of one transplant for life. One barrier to the induction of transplant tolerance in the clinic is T cell memory (Tmem). The intrinsic independence of Tmem from costimulation and their resistance to Tregs can explain the difficulty in inducing tolerance. Project 2 has identified an additional hurdle by which Tmem can antagonize the induction of transplant tolerance: a small number of Tmem can “infect” naïve T cells into acquiring memory-like features and resisting costimulation blockade (CoB) via a process of ‘linked-sensitization’. Once established, transplantation tolerance may exhibit vulnerabilities to its maintenance especially during settings of proinflammatory infection. Project 1 has identified heterogeneity in states of dysfunction achieved by polyclonal alloreactive T cells following CoB, with T cells specific for alloantigens that are rapidly downregulated in the graft following transplantation, and T cells with low affinity/avidity to graft antigens, retaining function despite CoB. These functional T cells do not pose a threat to the graft at steady state because they are controlled by Tregs. However, inflammatory cytokines elicited by some infections are known to destabilize Tregs, activate APCs and upregulate graft MHC, such that these T cells that retain function may mediate graft rejection. Both projects have identified a solution to these barriers/vulnerabilities. Project 2 found that exposing donor- reactive Tmem to a semi-allogeneic pregnancy re-programs Tmem into becoming susceptible to CoB. Project 1 shows that repeated injections of donor splenocytes can induce dysfunction in a wider repertoire of alloreactive T cells, including Tmem. The molecular mechanisms underlying the acquisition of dysfunction will be investigated and compared between projects, thus underscoring the synergy of the projects. The global hypothesis of the current submission is that understanding the mechanisms by which linked sensitization and heterogeneity in alloreactive T cell dysfunction prevent tolerance induction or break established tolerance, as well as the mechanisms by which exposure to pregnancy or to repeated donor splenocyte injections overcome these barriers, will help identify critical molecular drivers of tolerance, markers of robust versus unstable tolerance, and aid in the design of new therapeutic approaches to induce durable transplantation tolerance. Project 1 addresses the mechanisms by which the duration of alloantigen expression determines the level of T cell dysfunction post- CoB (Aim 1) and tests the hypothesis that low affinity/avidity alloreactive T cells are poised to mediate rejection during infections (Aim 2). Project 2 investigates the mechanism behind linked sensitization (Aim 1), and how CD8+ (Aim 2) and CD4+ (Aim 3) alloreactive Tmem are re-programmed by pregnancy.