Noninvasive Markers and Transplant Outcome in Humans

描述(申请人提供)：移植是治疗终末期心脏和终末期肾功能衰竭的理想疗法，但同种异体移植物的存活率和功能仍不理想。此次CTOT续签申请将建立在过去4年研究心脏和肾脏移植受者的生物标记物和损伤机制的结果基础上，以努力开发针对个别患者的治疗方法。压倒一切的临床假设是，在合理选择的非侵入性免疫监测的指导下，特别设计的治疗将改善心脏和肾脏移植受者的结果。这一假设将通过两项针对两个不同移植人群的研究来验证。研究概念1将检验这样的假设，即缺乏抗供体T细胞记忆将促进非致敏、低风险肾移植受者钙调神经磷酸酶抑制物(CNI)的安全消除。来自7个合作中心的活体供肾移植受者，在常规活检中没有临床急性排斥反应、供体特异性抗体或炎症，以及6个月后外周血中没有抗供体激活/记忆T细胞的证据，将随机接受他克莫司治疗或继续接受标准治疗。24个月时的肾功能和慢性损伤的组织学证据将作为终点。试验将在我们为正在进行的CTOT试验而建立的基础设施内进行。相关的机制研究将评估包括T细胞耗尽在内的定向抗记忆治疗对同种异体反应效应器T细胞库的影响，并将评估有无他克莫司时同种异体移植肝纤维化的分子基础。研究概念2将包括确定抗体介导的损伤(高PRA)的高风险候选心脏移植，并进行一项试点研究，以确定联合使用B细胞耗竭(利妥昔单抗)、IVIG血浆置换脱敏的安全性和有效性。这项研究将验证这样的假设，即脱敏将降低PRA，缩短心脏移植的等待时间，并导致可接受的一年移植物存活和功能。患者将从一个由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反应性T细胞和B细胞免疫，并将检验对供体抗原具有反应性的剩余B细胞和T细胞免疫记忆介导移植后损伤的假设。拟议的研究将解决肾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。 相关性：肾移植和心脏移植是器官衰竭的救命疗法，但移植的器官不会无限期存活。这项拟议工作的目标是1)测试改善移植结果(使器官寿命更长)的新方法，2)确定可改变的风险因素以改善结果，3)确定心脏或肾脏移植失败的原因，以便设计更好的治疗方法。

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.