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: 7293367
• 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/7293367
• 关键词: Achievement; Acute; Allograft Tolerance; Allografting; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Bone Marrow; Bone Marrow Transplantation; Cadaver; Chimerism; Chronic; Clinical; Clinical Medicine; Condition; Development; Disadvantaged; Doctor of Medicine; Drug toxicity; Engraftment; Equilibrium; Failure; Fertilization; General Hospitals; Goals; Grant; Hand; Head; Hematopoietic; Human; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Instinct; Institutes; Insulin; Ischemia; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney; Kidney Transplantation; Lead; Link; Living Donors; Macaca fascicularis; Maintenance; Malignant Neoplasms; Massachusetts; Measures; Memory; Metabolic; Methods; Modeling; Mus; Operative Surgical Procedures; Organ; Organ Procurements; Organ Transplantation; Outcome; Patients; Physiological reperfusion; Pilot Projects; Population; Primates; Protocols documentation; Rate; Regulation; Reperfusion Therapy; Research Personnel; Role; Survival Rate; T memory cell; T-Cell Activation; T-Lymphocyte; Talents; Testing; Therapeutic immunosuppression; Time; Tissue Donors; Translational Research; Transplantation; Transplantation Tolerance; Treatment Protocols; Work; base; caN protocol; clinical application; clinically relevant; conditioning; cytokine; day; exhaustion; experience; graft function; improved; in vivo; islet; islet allograft; kidney allograft; nonhuman primate; novel; professor; programs; research study; 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。 项目1：肾同种异体接受者的新型耐受策略（Cosimi，A。Benedict） 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，但在过去的十年中，长期同种异体移植生存尚未显着改善，这主要是由于慢性拒绝和转移后的恶性肿瘤，这都是归因于慢性免疫抑制。因此，特定的移植耐受性的诱导可能消除了常规免疫抑制疗法的大多数局限性仍然是一个主要目标。 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.最近，这在临床上应用于HLA认同和单倍型相同肾脏的受体。当前的制备方案的缺点是在器官移植前6天开始进行调节的要求，使其仅适用于同种异体同种异体移植物的接受者，并且仅在器官移植方面前瞻性。该项目的主要目的是制定一种新的方案，即“延迟的公差”方案，以扩展混合嵌合方法的临床适用性。在此方案中，接受者最初将接受常规免疫抑制的肾脏移植（KTX），然后在以后的某个时候接受非毛囊条件和DBMT。如果DBM在死者的初始器官采购时，该方案可能会将适用性扩展到所有先前移植同种异体移植物的接受者，包括已故捐赠者的器官的接受者。这种方法可能比我们当前的方法更有效，因为在没有促炎性细胞因子的情况下，建立了耐受性调节方案，这些因子可能会损害腹腔内植物时期的耐受性诱导。另一方面，如果延迟耐受性诱导，可以预测肾脏同种异体移植的存在可能会导致对供体抗原的敏感，而记忆T细胞激活增加。因此，为了建立“延迟的公差”协议，我们将具体做出：1）确定具有最小炎症反应的耐受性诱导的最佳时机，但记忆T细胞激活的可能性最小，但最少的可能性，2）评估要克服记忆T细胞反应的方法，并评估3）评估抗炎性药物对混合壳壳壳的添加的方法。将进行详细的机械研究，计划的分析应为合理地制定肾脏的耐受性策略不仅为肾脏，而且所有同种异体移植者接受者提供新的耐受性策略。