Determinants of T Cell Fate in Transplantation

移植中 T 细胞命运的决定因素

• 批准号: 7881608
• 负责人: Mandy L Ford
• 金额: $ 38.36万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-25 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7881608
• 关键词: Acute; Address; Antigens; Applications Grants; Blood Platelets; CD28 gene; CD8B1 gene; Cell physiology; Cells; Cessation of life; Chimerism; Clinic; Clinical; Communities; Dendritic Cells; Disease; Exposure to; Failure; Functional disorder; Goals; Graft Rejection; Graft Survival; Health; Hematopoietic; Immune; Immunity; Immunosuppression; Immunosuppressive Agents; Knowledge; Longevity; Mediating; Memory; Methods; Organ; Outcome; Pathway interactions; Process; Protocols documentation; Recording of previous events; Refractory; Regimen; Relative (related person); Resistance; Role; Signal Pathway; Signal Transduction; Staging; Survival Rate; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; TNFRSF5 gene; TNFSF5 gene; Terminal Disease; Therapeutic; Thromboembolism; Translations; Transplant Recipients; Transplantation; Transplantation Tolerance; Viral; allograft rejection; design; improved; in vivo; insight; interest; meetings; pathogen; prevent; programs; response; success

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.

描述（由适用提供）：移植是许多形式的终末期器官疾病的首选治疗方式。移植成功的成功是基于控制T细胞依赖拒绝过程的治疗方法。这是宽容诱导策略的统一目标是选择性地灭活或删除供体反应性T细胞。 CD28/B7和CD154/CD40途径的瞬态阻滞在NA¿VE受体中的公差方案中表现出了很大的希望，尤其是那些影响混合造血嵌合和强大的供体特异性耐受性的受体。不幸的是，是这种方法的基石的抗CD154 mAB会引起血小板功能障碍和血栓主义。另外，异源免疫力导致供体特异性记忆T细胞的存在列出了移植耐受性的潜在障碍。这两个因素提出的挑战是必须应对影响移植耐受性的挑战，就是成为临床现实。尽管对这些途径有多年的兴趣，但我们对CD28和CD154桶协同促进NA¿VE供体反应性T细胞的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，我们可能会发现新的机会来编程供体特定的T细胞来执行死亡计划，而不是导致拒绝的扩展和分化路径。尽管在定义CD40传递信号的多种机制方面取得了很大进展，但目前我们几乎没有深入了解哪些CD40相关的适配器分子和信号通路必须中断以促进NA¿VE供体反应性T细胞的缺失。此外，现在已经良好的记忆T细胞不太容易受到CD28和CD40封锁的影响。这就是移植受者的免疫病史以及各个隔室内的供体反应记忆T细胞的水平（CD4+或CD8+ TEM或TCM）可能决定成功或尝试耐受性诱导甚至免疫抑制尝试成功的可能性或失败。通过了解由各种记忆T细胞子集介导的召回响应的功能，共刺激和信号传导要求，我们可能能够量身定制耐受性诱导方法，以控制特定供体受体组合的主要记忆形式。摘要摘要：移植代表了许多终末疾病的治愈方法。但是，移植受者需要终身免疫抑制，以防止同种异体移植的免疫抑制。该赠款提案的目的是了解免疫细胞（T细胞）需要拒绝移植的信号。有了这些知识，我们将设计用于控制这些细胞的方法，以开发诱导长期移植的方法，而无需有毒免疫抑制方案。 在过去十年的目的地急性排斥率急剧下降，临床移植的长期叙事长期移植物存活率几乎没有改变，激励移植社区开发耐受性诱导策略，从而广泛改善了长期净健康状况。鉴于T细胞在移植排斥反应中的核心作用，耐受性诱导策略的统一目标是选择性地失活或删除供体反应性T细胞。这里提出的机械研究将描绘移植耐受性中T细胞命运的决定剂。