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之上。耐受诱导策略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 通路在自然耐受方案中显示出巨大的前景。不幸的是，作为这种方法基石的抗 CD154 mAb 会导致血小板功能障碍和血栓栓塞。因此，尽管多年来人们一直对共刺激阻断诱导移植耐受成为现实，但异源免疫对移植耐受构成了强有力的障碍。在这些途径中，我们了解 CD28 和 CD154 阻断协同促进 na¿供体反应性 T 细胞仍然非常不完整，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。尽管在定义 CD40 转导信号的多种机制方面已经取得了相当大的进展，但目前我们对其中哪一种机制知之甚少。必须中断 CD40 相关接头分子和信号传导途径以促进 na¿此外，现在已经确定记忆 T 细胞不太容易受到 CD28 和 CD40 阻断的影响，因此，移植受者的免疫史和供体交叉反应记忆 T 细胞的水平。通过了解记忆反应介导的功能、共刺激和信号传导要求，不同区室（CD4+或CD8+TEM或TCM）内的细胞可能决定耐受诱导甚至免疫抑制尝试成功或失败的可能性。然而，对于不同的记忆 T 细胞亚群，我们或许能够定制耐受诱导方法来控制特定供体-受体组合的主要记忆形式。这项拨款提案的目标是了解免疫细胞（T 细胞）排斥移植物所需的信号，我们将设计控制这些细胞的方法，以开发诱导持久移植的方法。接受无需要有毒的免疫抑制方案。 项目叙述 尽管急性排斥率大幅下降，但临床移植中的长期移植物存活率在过去十年中变化不大，这促使移植界制定耐受诱导策略，以广泛改善长期净健康结果。移植排斥中的 T 细胞，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。此处提出的机制研究将描述移植耐受中 T 细胞命运的决定因素。