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: 7684588
• 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/7684588
• 关键词: Acute; Allograft Tolerance; Allografting; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Biostatistics Core; Bone Marrow Transplantation; Chimerism; Chronic; Clinical; Development; Disadvantaged; Drug toxicity; Engraftment; Equilibrium; Failure; Fertilization; Goals; Grant; Hand; Human; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Institutes; Insulin; Ischemia; Islet Cell; Islets of Langerhans Transplantation; Kidney; Kidney Transplantation; Lead; Link; Living Donors; Macaca fascicularis; Maintenance; Malignant Neoplasms; Measures; Memory; Metabolic; Methods; Mus; Organ; Organ Procurements; Organ Transplantation; Outcome; Primates; Protocols documentation; Regulation; Reperfusion Therapy; Research; Role; Survival Rate; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Tissue Donors; Transplantation; Transplantation Tolerance; Treatment Protocols; base; clinical application; clinically relevant; conditioning; cytokine; exhaustion; graft function; immunopathology; 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. PROJECT 1: Novel Tolerance Strategy in Renal Allograft Recipients (Cosimi, A. Benedict) PROJECT 1 DESCRIPTION (provided by applicant): Despite improvement in short-term results through the use of new immunosuppressive agents, long-term allograft survival has not improved significantly over the past decade, due predominantly to chronic rejection but also to infection and post-transplant malignancies, all attributable to chronic immunosuppression. Therefore, induction of specific transplantation tolerance, which might eliminate most limitations of conventional immunosuppressive therapy remains a major goal. Based upon the mixed chimerism approach, which was first demonstrated to be an effective means of inducing allograft tolerance in mice, we first developed a clinically relevant non-myeloablative preparative regimen that permitted the induction of mixed chimerism and renal allograft tolerance following donor bone marrow transplantation (DBMT) in MHC fully mismatched cynomolgus monkeys. More recently, this was applied clinically to recipients of HLA-identical and haplo-type identical kidneys. A disadvantage of the current preparative regimen is the requirement for conditioning beginning 6 days prior to organ transplantation, making it applicable only for recipients of living donor allografts and only prospectively with respect to the organ transplant. The major goal of this project is to develop a novel regimen, the "Delayed Tolerance" protocol to extend the clinical applicability of the mixed chimerism approach. In this protocol, recipients would initially undergo kidney transplantation (KTx) with conventional immunosuppression and then receive non-myeloablative conditioning and DBMT sometime later. This protocol could potentially extend the applicability to all recipients of previously transplanted allografts, including recipients of organs from deceased donors, if DBM is cryopreserved at the time of initial organ procurement from the deceased donor. This approach could prove to be even more effective than our current approach, since the tolerance conditioning regimen is instituted in the absence of pro-inflammatory cytokines that may impair tolerance induction in the peritransplant period. On the other hand, if tolerance induction is delayed, it might be predicted that the presence of the renal allograft could result in sensitization to donor antigen with memory T cell activation increasing. Therefore, to establish the "Delayed Tolerance" protocol, we will specifically: 1) identify the optimal timing for tolerance induction with minimal inflammatory responses, yet least likelihood of memory T cell activation, 2) evaluate methods to overcome memory T cell responses and 3) evaluate the addition of anti-inflammatory agents to the mixed chimerism protocol. Detailed mechanistic studies will be performed and the analyses planned should provide clinically relevant information for rationally developing new tolerance strategies for not only kidney but also all allograft recipients.

描述（由申请人提供）：尽管在过去二十年中移植后早期存活率有所提高，但既往成功的肾移植受者每年3- 5%的持续流失率继续限制长期结局。胰岛移植的长期结果是完全不可接受的，只有10%的接受者在五年内保持无胰岛素。在胰岛中，由于胰岛细胞质量不足而导致的代谢衰竭可能是长期移植功能的重要障碍。由于慢性排斥反应、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肾和胰岛移植中长期施用免疫抑制剂的局限性。因此，移植的最终目标是在没有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体中进行测试，但在人体中实现真正的耐受性仍然存在重大障碍。这项多项目资助的主要目标是通过定义诱导对肾脏和胰岛同种异体移植物持久耐受的基本条件，以及定义炎症和记忆T细胞在耐受的主要障碍中的作用，来改善肾脏和胰岛移植后的结果。我们的中心假设是，早期促炎反应在很大程度上归因于供体组织的缺血-再灌注和缺氧损伤，从而激发了不利形式的抗供体免疫，从而引起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随后扩展，以及新获得的供体反应性记忆T细胞的移植后发育。因此，我们假设促-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的主要障碍。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，以有利于调节和长期耐受，同时考虑到胰岛和肾移植背景下的炎症和记忆相关的耐受障碍。将两个相互关联的体内项目的具体目标和机制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攻击性和记忆反应、T细胞调节和耐受诱导的平衡的相关性和相互关系。因此，它应该是可能的定义和系统地应用干扰的先天性和适应性免疫反应，导致耐受灵长类动物同种异体移植受体。此外，该计划将导致项目1与项目2开发的最佳耐受诱导方案的交叉和共享。 项目1：肾移植受者的新耐受策略（Cosimi，A.本尼迪克特） 项目1描述（由申请人提供）：尽管通过使用新的免疫抑制剂改善了短期结果，但在过去十年中，长期同种异体移植物存活率并未显著改善，主要原因是慢性排斥反应，但也有感染和移植后恶性肿瘤，所有这些都可归因于慢性免疫抑制。因此，诱导特异性移植耐受，这可能会消除大多数常规免疫抑制治疗的局限性仍然是一个主要目标。基于混合嵌合体方法，其首次被证明是在小鼠中诱导同种异体移植物耐受的有效手段，我们首先开发了一种临床相关的非清髓性准备方案，其允许在MHC完全不匹配的食蟹猴中在供体骨髓移植（DBMT）后诱导混合嵌合体和肾同种异体移植物耐受。最近，这在临床上应用于HLA相同和单倍型相同肾脏的受体。目前的准备方案的缺点是需要在器官移植前6天开始预处理，使得其仅适用于活体供体同种异体移植物的受体，并且仅对器官移植具有前瞻性。该项目的主要目标是开发一种新的方案，即“延迟耐受”方案，以扩展混合嵌合体方法的临床适用性。在该方案中，受者最初将接受常规免疫抑制的肾移植（KTx），然后在稍后接受非清髓性预处理和DBMT。如果DBM在从已故供体首次获取器官时被冷冻保存，则该方案可能将适用性扩展到所有先前移植的同种异体移植物的受体，包括来自已故供体的器官的受体。这种方法可能被证明比我们目前的方法更有效，因为耐受性调节方案是在不存在促炎细胞因子的情况下建立的，促炎细胞因子可能会损害围移植期的耐受性诱导。另一方面，如果耐受诱导延迟，则可以预测肾移植物的存在可能导致对供体抗原的致敏，记忆T细胞活化增加。因此，为了建立“延迟耐受性”方案，我们将具体地：1）确定具有最小炎症反应但记忆T细胞活化的可能性最小的耐受性诱导的最佳时机，2）评价克服记忆T细胞反应的方法，和3）评价向混合嵌合方案中添加抗炎剂。将进行详细的机制研究，计划的分析应提供临床相关信息，以合理开发新的耐受策略，不仅适用于肾脏，而且适用于所有同种异体移植受者。