Noninvasive Markers and Transplant Outcome in Humans

人类非侵入性标志物和移植结果

• 批准号: 7919132
• 负责人: Peter Scott Heeger
• 金额: $ 92.06万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919132
• 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）：移植是终末期心脏衰竭和终末期肾衰竭的理想疗法，但同种异体移植物的存活和功能仍然不理想。这一 CTOT 更新应用将建立在过去 4 年研究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，努力开发适合个体患者的治疗方法。最重要的临床假设是，在合理选择的无创免疫监测指导下专门设计的疗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 2 个不同移植群体的 2 项研究进行检验。研究概念 1 将检验以下假设：抗供体 T 细胞记忆的缺失将有助于在非致敏、低风险同种异体肾移植受者中安全消除钙调神经磷酸酶抑制剂 (CNI)。来自 7 个合作中心的活体供肾同种异体移植物的受者，如果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 个月时外周血中没有抗供体引发/记忆 T 细胞的证据，将被随机分配到消除他克莫司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用作终点。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，并进行一项试点研究，以确定使用 B 细胞耗竭（利妥昔单抗）和 IVIG 血浆置换相结合的脱敏的安全性和有效性。该研究将检验脱敏将降低 PRA、缩短心脏移植等待时间并带来可接受的 1 年移植物存活和功能的假设。患者将从由 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损伤的假设。拟议的研究将解决肾脏和心脏移植中的临床相关问题，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挽救生命的治疗方法，但移植的器官不能无限期地持续。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) 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。