Noninvasive Markers and Transplant Outcome in Humans

描述（由申请人提供）：移植是终末期心脏和终末期肾衰竭的理想治疗方法，但同种异体移植的生存和功能仍然不理想。这项CTOT更新申请将建立在过去4年对心脏和肾脏移植受者的生物标志物和损伤机制的研究结果的基础上，以开发针对个体患者的治疗方法。最重要的临床假设是，在合理选择非侵入性免疫监测的指导下，专门设计的治疗方法将改善心脏和肾脏移植受者的预后。这一假设将通过针对两个不同移植人群的两项研究进行验证。研究概念1将验证一个假设，即在非致敏、低风险的同种异体肾移植受者中，缺乏抗供体T细胞记忆将促进钙调磷酸酶抑制剂（CNI）的安全消除。来自7个合作中心的活体供体异体肾移植受者，在6个月时没有临床急性排斥反应、供体特异性抗体或炎症，并且在外周血中没有抗供体启动/记忆T细胞的证据，将被随机分配到他克莫司消除组或继续接受标准治疗。肾功能和慢性损伤24个月时的组织学证据将作为终点。试验将在我们为正在进行的CTOT试验建立的基础设施内进行。相关的机制研究将评估包括T细胞耗竭在内的靶向抗记忆疗法对同种异体反应效应T细胞库的影响，并将评估他克莫司存在或不存在时同种异体移植物纤维化的分子基础。研究概念2将涉及识别抗体介导损伤（高PRA）高风险的心脏移植候选人，并进行一项试点研究，以确定使用B细胞消耗（利妥昔单抗）和IVIG血浆置换联合脱敏的安全性和有效性。该研究将验证脱敏会降低PRA，缩短心脏移植等待时间，并导致可接受的1年移植物存活和功能的假设。患者将从22个北美心脏移植中心组成的强大联盟中招募，该联盟是为正在进行的心脏移植CTOT05研究而开发的。相关的机制研究将确定脱敏方案如何影响预先形成的同种异体T细胞和B细胞免疫，并将检验对供体抗原具有反应性的残余B细胞和T细胞免疫记忆介导移植后同种异体移植物损伤的假设。拟议的研究将解决肾脏和心脏移植的临床相关问题，并将提供新的信息，无论结果如何。

DESCRIPTION (provided by applicant): Transplantation is the ideal therapy for end stage heart and end stage kidney failure, but allograft survival and function remain suboptimal. This CTOT renewal application will build upon the findings resulting from the previous 4 years of studying biomarkers and mechanisms of injury in heart and kidney transplant recipients in an effort to develop therapies tailored to individual patients. The overriding clinical hypothesis is that specifically designed therapies guided by rationally chosen noninvasive immune monitoring will improve outcomes in heart and kidney transplant recipients. This hypothesis will be tested through 2 studies targeting 2 separate transplant populations. Study Concept 1 will test the hypothesis that the absence of anti-donor T cell memory will facilitate safe calcineurin inhibitor (CNI) elimination in nonsensitized, low risk recipients of kidney allografts. Recipients of living donor kidney allografts from 7 collaborating centers, without clinical acute rejection, donor-specific antibody or inflammation on protocol biopsy, and without evidence of anti-donor primed/memory T cells in their peripheral blood at 6 months will be randomized to tacrolimus elimination or remain on standard therapy. Renal function and histologic evidence of chronic injury at 24 months will be used as endpoints. The trial will be done within the established infrastructure built by us for the ongoing CTOT trials. The associated mechanistic studies will assess the impact of targeted anti- memory therapy including T cell depletion on the alloreactive effector T cell repertoire and will evaluate the molecular basis of allograft fibrosis in the presence or absence of tacrolimus. Study concept 2 will involve identifying heart transplant candidates at high risk for antibody mediated injury (high PRA) and performing a pilot study to determine the safety and efficacy of desensitization using a combination of B cell depletion (rituximab), IVIG plasmapheresis. The study will test the hypothesis that desensitization will lower PRA, diminish the waiting time to heart transplantation and result in acceptable 1 year graft survival and function. Patients will be enrolled from within a powerful consortium of 22 North American heart transplant centers that was developed for the ongoing heart transplantation CTOT05 study. Associated mechanistic studies will determine how the desensitization protocol impacts preformed alloreactive T and B cell immunity and will test the hypothesis that residual B and T cell immune memory with reactivity to donor antigens mediates post-transplant allograft injury. The proposed studies will address clinically relevant questions in kidney and heart transplantation and will provide novel information regardless of outcome. RELEVANCE: Kidney transplantation and heart transplantation are lifesaving treatments for organ failure, but the transplanted organs do not last indefinitely. The goals of the proposed work are 1) to test new approaches for improving transplant outcomes (making organs last longer), 2) to identify modifiable risk factors to improve outcomes and 3) determine why the heart or kidney transplants fail so as to design better treatments.