Individualizing Therapy for Kidney and Heart Transplant Recipients

肾脏和心脏移植受者的个体化治疗

• 批准号: 8100584
• 负责人: Peter Scott Heeger
• 金额: $ 995.52万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-13 至 2012-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100584
• 关键词: Acute; Address; Allografting; American; Antibodies; Antigens; Arts; B-Lymphocytes; Biological Assay; Biological Markers; Biopsy; Calcineurin inhibitor; Canada; Cardiac; Chronic; Clinical; Collaborations; Control Groups; Enrollment; Environment; Fibrosis; Funding; Goals; Graft Survival; Heart; Heart Transplantation; Histologic; Human; Immune; Immunity; Immunologic Monitoring; Individual; Inflammation; Injury; Intention; Intravenous Immunoglobulins; Kidney; Kidney Failure; Kidney Transplantation; Leadership; Living Donors; Mediating; Memory; Molecular; Organ; Organ Transplantation; Organ failure; Outcome; Patients; Phase; Pilot Projects; Plasmapheresis; Population; Protocols documentation; Randomized; Renal function; Research Infrastructure; Research Personnel; Residual state; Risk; Risk Factors; Safety; Solid; Staging; T memory cell; T-Cell Depletion; T-Lymphocyte; Tacrolimus; Testing; Time; Transplant Recipients; Transplantation; Work; base; clinically relevant; desensitization; design; drug withdrawal; experience; high risk; improved; kidney allograft; modifiable risk; novel; novel strategies; peripheral blood; response; rituximab; success; therapy design; therapy development

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.

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，但同种异体移植物存活率和功能仍不理想。该CTOT更新申请将建立在过去4年研究心脏和肾脏移植受者损伤的生物标志物和机制的结果的基础上，以努力开发针对个体患者的治疗方法。最重要的临床假设是，在合理选择的非侵入性免疫监测指导下，专门设计的治疗将改善心脏和肾脏移植受者的结局。该假设将通过针对2个单独移植人群的2项研究进行检验。研究概念1将检验以下假设：在非致敏、低风险肾移植受者中，抗供体T细胞记忆的缺乏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肾同种异体移植物的受体，在方案活检中没有临床急性排斥反应、供体特异性抗体或炎症，并且在6个月时在其外周血中没有抗供体致敏/记忆T细胞的证据，将被随机分配到他克莫司消除或保持标准治疗。将使用24个月时的肾功能和慢性损伤的组织学证据作为终点。该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靶向抗记忆治疗（包括T细胞耗竭）对同种异体反应性效应T细胞库的影响，并将评估在存在或不存在他克莫司的情况下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者，并进行初步研究，以确定联合使用B细胞耗竭（利妥昔单抗）和IVIG血浆置换进行脱敏的安全性和有效性。该研究将检验以下假设：脱敏将降低PRA，减少心脏移植的等待时间，并导致可接受的1年移植物生存和功能。患者将从一个由22家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CTOT 05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和B细胞免疫，并将检验对供体抗原具有反应性的残留B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。 相关性：肾移植和心脏移植是器官衰竭的救命疗法，但移植的器官不能无限期地维持。拟议工作的目标是1）测试改善移植结果的新方法（使器官寿命更长），2）识别可改变的风险因素以改善结果，以及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。