Determinants of T Cell Fate in Transplantation

描述(申请人提供)：移植是许多形式的终末期器官疾病的首选治疗方式。移植的成功建立在控制T细胞依赖的排斥过程的治疗方法上。因此，耐受诱导策略的一个统一目标是选择性地灭活或删除供体反应性T细胞。瞬时阻断CD28/B7和CD154/CD40通路已显示出在初治受者耐受方案中的巨大前景，特别是那些诱导混合造血细胞嵌合体和供者特异性耐受的方案。不幸的是，抗CD154单抗是这种方法的基石，会导致血小板功能障碍和血栓栓塞症。此外，异种免疫导致的供者特异性记忆T细胞的存在是移植耐受的有效障碍。因此，如果共刺激阻断诱导移植耐受成为临床现实，这两个因素是必须应对的挑战。尽管多年来人们对这些途径感兴趣，但我们对CD28和CD154阻断协同促进NA-供体反应性T细胞删除的机制的了解仍然很不完整。通过扩展我们对这一过程的了解，我们可能会发现新的机会来编程原始的供者特异性T细胞来执行死亡程序，而不是导致排斥的扩增和分化途径。虽然在定义CD40转导信号的多种机制方面已经取得了相当大的进展，但目前我们对哪些CD40相关的接头分子和信号通路必须被阻断以促进初始供体反应性T细胞的删除知之甚少。此外，记忆T细胞不太容易受到CD28和CD40阻断的影响，这一点现在已经得到证实。因此，移植受者的免疫史和不同间隔内供者交叉反应记忆T细胞的水平(CD4+或CD8+透射电子显微镜或Tcm)可能决定耐受诱导或甚至免疫抑制尝试的成功或失败的可能性。通过了解不同记忆T细胞亚群介导的回忆反应的功能、共刺激和信号要求，我们可能能够定制耐受诱导方法来控制特定供受者组合的主要记忆形式。通俗易懂：移植是治愈许多绝症的有效方法。然而，移植受者需要终生免疫抑制以防止同种异体移植物的免疫排斥反应。这项拨款提案的目标是了解免疫细胞(T细胞)拒绝移植所需的信号。有了这些知识，我们将设计方法来控制这些细胞，以开发诱导长期移植接受的方法，而不需要有毒的免疫抑制方案。 项目简介临床移植的长期移植物存活率在过去十年中变化不大，尽管急性排斥率大幅下降，促使移植社区开发出广泛改善长期净健康结果的耐受诱导策略。鉴于T细胞在移植排斥反应中的中心作用，耐受诱导策略的一个统一目标是选择性地灭活或删除供体反应性T细胞。这里提出的机制研究将描绘T细胞在移植耐受中命运的决定因素。

DESCRIPTION (provided by applicant): Transplantation is the preferred mode of therapy for many forms of end-stage organ disease. Success in transplantation has been built upon therapeutic approaches to control the T cell-dependent process of rejection. Thus, a unifying goal of tolerance induction strategies is to selectively inactivate or delete donor- reactive T cells. Transient blockade of the CD28/B7 and CD154/CD40 pathways has shown great promise in tolerance protocols in na¿ve recipients, particularly those that induce mixed hematopoietic chimerism and robust donor-specific tolerance. Unfortunately, the anti-CD154 mAbs that are a cornerstone of this approach cause platelet dysfunction and thromboembolism. In addition, the presence of donor-specific memory T cells as a result of heterologous immunity present a potent barrier to transplantation tolerance. Thus, these two factors present challenges that must be met if costimulation blockade to induce transplantation tolerance is to become a clinical reality. Despite years of interest in these pathways, our knowledge of the mechanisms by which CD28 and CD154 blockade synergize to promote the deletion of na¿ve donor-reactive T cells remains very incomplete. By extending our knowledge of this process, we may identify new opportunities to program na¿ve donor-specific T cells to execute a death program rather than an expansion and differentiation path that leads to rejection. While there has been considerable progress in defining the multiple mechanisms by which CD40 transduces signals, at present we have little insight into which of the CD40-associated adaptor molecules and signaling pathways must be interrupted to promote deletion of na¿ve donor-reactive T cells. Furthermore, it is now well-established that memory T cells are less susceptible to the effects of CD28 and CD40 blockade. Thus, the immune history of a transplant recipient and levels of donor-cross-reactive memory T cells within the various compartments (CD4+ or CD8+ TEM or TCM) may dictate the likelihood of success or failure of attempts at tolerance induction or even immunosuppression. By understanding the functions, costimulatory and signaling requirements for recall responses mediated by the various memory T cell subsets, we may be able to tailor tolerance induction approaches to control the predominant forms of memory for specific donor- recipient combinations. Lay Summary: Transplantation represents a cure for many terminal diseases. However, transplant recipients require lifelong immunosuppression to prevent immunological rejection of the allograft. The goal of this grant proposal is to understand the signals that immune cells (T cells) require to reject transplants. With this knowledge, we will design methods to control these cells to develop methods of inducing long- lasting transplant acceptance without the need for toxic immunosuppressive regimens. PROJECT NARRATIVE Long-term graft survival rates in clinical transplantation have changed little during the last decade despite dramatic reductions in acute rejection rates, motivating the transplant community to develop tolerance induction strategies that broadly improve long-term net health outcomes. Given the central role of T cells in transplant rejection, a unifying goal of tolerance induction strategies is to selectively inactivate or delete donor-reactive T cells. Mechanistic studies proposed here will delineate the determinants of T cell fate in transplant tolerance.