Determinants of T Cell Fate in Transplantation

描述（由申请人提供）：移植是多种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细胞依赖性排斥过程的治疗方法上。因此，耐受诱导策略的统一目标是选择性地扩增或删除供体反应性T细胞。CD 28/B7和CD 154/CD 40通路的瞬时阻断在初次接受者的耐受方案中显示出很大的希望，特别是那些诱导混合造血嵌合体和强大的供体特异性耐受的方案。不幸的是，抗CD 154单克隆抗体是这种方法的基石，导致血小板功能障碍和血栓栓塞。此外，作为异源免疫的结果，供体特异性记忆T细胞的存在为移植耐受提供了有力的屏障。因此，这两个因素提出了挑战，必须满足，如果共刺激阻断诱导移植耐受成为临床现实。尽管多年来对这些途径感兴趣，但我们对CD 28和CD 154阻断协同促进幼稚供体反应性T细胞缺失的机制的了解仍然非常不完整。通过扩展我们对这一过程的了解，我们可以确定新的机会来编程幼稚供体特异性T细胞执行死亡程序，而不是导致排斥反应的扩增和分化路径。虽然在确定CD 40转导信号的多种机制方面取得了相当大的进展，但目前我们对哪些CD 40相关的衔接分子和信号通路必须被中断以促进幼稚供体反应性T细胞的缺失几乎没有了解。此外，现在已经确定记忆T细胞对CD 28和CD 40阻断的影响不太敏感。因此，移植受体的免疫史和各种隔室（CD 4+或CD 8 + TEM或TCM）内的供体交叉反应性记忆T细胞的水平可以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。通过了解由各种记忆T细胞亚群介导的回忆应答的功能、共刺激和信号传导要求，我们可能能够定制耐受诱导方法以控制特定供体-受体组合的记忆的主要形式。简介：移植是治疗许多绝症的方法。然而，移植受者需要终身免疫抑制以防止同种异体移植物的免疫排斥。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，我们将设计控制这些细胞的方法，以开发诱导持久移植接受而不需要毒性免疫抑制方案的方法。 在过去的十年中，尽管急性排斥反应率大幅下降，但临床移植的长期移植物存活率变化不大，这促使移植界制定耐受诱导策略，广泛改善长期净健康结果。鉴于T细胞在移植排斥中的核心作用，耐受诱导策略的统一目标是选择性地抑制或删除供体反应性T细胞。机制的研究提出这里将描绘T细胞的命运在移植耐受的决定因素。

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.