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

描述(由申请人提供)：尽管移植后早期存活率在过去20年中有所改善，但在以前成功的肾移植受者中，每年3-5%的无情流失率继续限制着长期结果。胰岛移植的长期结果是不可接受的，只有10%的受者在五年内保持无胰岛素状态。在胰岛中，由于胰岛细胞质量不足导致的代谢衰竭可能是长期移植功能的重要障碍。由于慢性排斥、感染、药物毒性和恶性肿瘤导致的晚期同种异体移植失败，强调了长期应用免疫抑制在肾和胰岛移植中的局限性。因此，移植的最终目的是在不维持免疫抑制的情况下实现长期植入。试点临床耐受性方案目前正在人类身上进行测试，但在人类身上实现真正的耐受性仍然存在重大障碍。这一多项目赠款的主要目标是通过确定诱导对同种异体肾和胰岛移植持久耐受的基本条件，以及确定炎症和记忆T细胞在耐受的主要障碍中的作用，来改善肾和胰岛移植后的结果。我们的中心假设是，早期的促炎反应在很大程度上是由于供体组织的缺血再灌注和缺氧损伤引起的，激发了不利形式的抗供体免疫，从而引发了急性临床或亚临床排斥反应，并夸大了先前存在的供体反应性记忆的后续扩展，以及移植后新获得的供体反应性记忆T细胞的发展。因此，我们假设，亲至抗炎细胞因子和抗供体记忆反应的不利平衡是诱导和维持耐受性的主要障碍。考虑到胰岛和肾移植中与炎症和记忆相关的耐受障碍，我们提出了新的和相互关联的策略来改变同种免疫反应的平衡，以利于调节和长期耐受。将这两个相互关联的体内项目的具体目标与机制研究联系起来的基本原理是，我们现在有了工具来测试炎症反应与攻击性反应和记忆反应的平衡、T细胞调节和耐受诱导的相关性和相互关系。因此，应该有可能定义并系统地应用导致灵长类同种异体移植受者耐受的先天和获得性免疫反应的扰动。此外，该计划将导致从项目1和项目2发展出的最佳耐受性诱导方案的各方面的交叉受精和共享。

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.