Inflammation and T Cell Memory: Inter-related Barriers to Allograft Tolerance

炎症和 T 细胞记忆：同种异体移植耐受的相互关联的障碍

• 批准号: 7928084
• 负责人: TERRY B. STROM
• 金额: $ 150万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-20 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7928084
• 关键词: Acute; Allograft Tolerance; Allografting; Anti-Inflammatory Agents; Anti-inflammatory; Chronic; Clinical; Development; Drug toxicity; Engraftment; Equilibrium; Failure; Fertilization; Goals; Grant; Human; Immune response; Immunity; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Insulin; Ischemia; Islet Cell; Islets of Langerhans Transplantation; Kidney; Kidney Transplantation; Lead; Link; Maintenance; Malignant Neoplasms; Measures; Memory; Metabolic; Outcome; Primates; Protocols documentation; Regimen; Regulation; Regulatory T-Lymphocyte; Reperfusion Therapy; Role; Survival Rate; T cell response; T memory cell; Testing; Tissue Donors; Transplantation; cytokine; exhaustion; graft function; improved; in vivo; islet; islet allograft; kidney allograft; novel; programs; response; tool

DESCRIPTION (provided by applicant): Despite improvements in early post-transplant survival rates over the last two decades, a relentless annual attrition rate of 3-5 % in recipients of previously successful renal allografts continues to limit longer term outcomes. Long term outcomes with islet transplantation are simply unacceptable with only 10% of recipients remaining insulin free at five years. In islets metabolic exhaustion due to an inadequate islet cell mass may be an important impediment to long term graft function. Late allograft failure, resulting from chronic rejection, infection, drug toxicity, and malignancies emphasizes the limitations of chronically administered immunosuppression in kidney and islet transplantations. Therefore the ultimate goal of transplantation is to achieve long-term engraftment without maintenance immunosuppression. Pilot clinical tolerance protocols are currently being tested in humans, but there remain substantial barriers to achieving true tolerance in humans. The major objective of this Multi-Project grant is to improve the outcome following kidney and islet transplantation by defining the essential conditions for induction of durable tolerance to kidney and islet allografts, and defining the roles of inflammation and memory T cells in being major barriers to tolerance. Our central hypothesis is that the early pro-inflammatory responses due in large measure to ischemia-reperfusion and anoxic injury to the donor tissues incites adverse forms of anti-donor immunity, thereby provoking acute clinical or subclinical rejection and exaggerating the subsequent expansion of pre-existing donor reactive memory, and post transplant development of newly acquired donor reactive memory T cells. Thus, we hypothesize that an adverse balance of pro- to anti-inflammatory cytokines and anti-donor memory responses represent major obstacles to the induction and maintenance of tolerance. We propose novel and inter-related strategies to alter the balance of the alloimmune response to favor regulation and long-term tolerance taking into consideration the inflammatory- and memory-related barriers to tolerance in the context of islet and kidney transplantation. The rationale linking the specific aims of the two interrelated in vivo projects and the mechanistic studies is that we now have the tools to test the relevance and inter-relationship of inflammatory responses to the balance of aggressive and memory responses, T cell regulatory and tolerance induction. It, therefore, should be possible to define and systematically apply the perturbations of the innate and adaptive immune response that lead to tolerance in primate allograft recipients. Moreover, the Program will lead to cross-fertilization and sharing of facets of the best tolerance inducing regimens developing from Project 1 with those of Project 2.

描述（由申请人提供）：尽管过去二十年来移植后早期存活率有所改善，但以前成功的肾同种异体移植物接收者的年度流失率为3-5％继续限制长期结局。胰岛移植的长期结局根本是无法接受的，只有10％的接受者在五年内保持不含胰岛素。在胰岛中，由于不充分的胰岛细胞质量而导致的代谢疲劳可能是长期移植功能的重要障碍。慢性排斥反应，感染，药物毒性和恶性肿瘤引起的晚期同种异体失败强调了肾脏和胰岛移植中长期给予免疫抑制的局限性。因此，移植的最终目标是在不维持免疫抑制的情况下实现长期植入。当前正在人类中测试了试点临床容忍方案，但是在人类中实现真正的耐受性仍然存在很大的障碍。这种多项目赠款的主要目的是通过定义诱导肾脏和胰岛同种异体耐受性的基本条件，并确定炎症和记忆T细胞在耐受性的主要障碍中的作用，从而改善肾脏和胰岛移植后的结果。我们的核心假设是，早期的促炎反应在很大程度上归因于缺血 - 重新灌注和对供体组织的缺氧损伤会激发抗抑制免疫的不利形式，从而引发了急性临床或亚临床抑制作用，从而引发了预测供体的供电术中的供体供电术的后续供应术中的新型供体供电术的扩张，并夸大了新的反应式供电术的新型供电术。因此，我们假设抗炎细胞因子和抗抑制记忆反应的不利平衡代表了耐受性诱导和维持的主要障碍。我们提出了新颖的和相关的策略，以改变同种免疫反应的平衡，以考虑在胰岛和肾脏移植的背景下，考虑到炎症和记忆相关的耐受性障碍。将两个相互关联的体内项目的特定目的和机械研究联系起来的基本原理是，我们现在有工具来测试炎症反应与侵略性和记忆反应，T细胞调节性和耐受性诱导平衡的相关性和相互关系。因此，应该有可能定义并系统地应用天生和适应性免疫反应的扰动，从而导致灵长类移植受体的耐受性。此外，该计划将导致与项目2的最佳公差相互耐受性诱导方案的交叉利用和共享。