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）：移植是终阶段心脏和末端肾脏衰竭的理想疗法，但同种异体移植的存活率和功能仍然是最佳的。这种CTOT更新应用将建立在过去4年来研究生物标志物和心脏和肾脏移植接受者损伤机制的发现上，以开发针对个别患者量身定制的疗法。最重要的临床假设是，以合理选择的非侵入性免疫监测为指导的专门设计的疗法将改善心脏和肾脏移植受者的预后。该假设将通过针对2个单独的移植人群的2项研究来检验。研究概念1将检验以下假设：缺乏抗抑制性T细胞记忆将促进肾脏同种异体移植物的非敏化，低风险受体中安全钙调神经蛋白抑制剂（CNI）消除。来自7个合作中心的活供体肾脏同种异体移植物，没有临床急性排斥反应，供体特异性抗体或对方案活检的炎症，并且没有证据表明在6个月时在其外周血液中抗抑制PRIMED/记忆T细胞的证据将被随机化为消除克罗伊龙或继续进行标准治疗。 24个月时慢性损伤的肾功能和组织学证据将用作终点。该试验将在我们为正在进行的CTOT试验的既定基础设施中进行。相关的机械研究将评估靶向抗记忆疗法的影响，包括T细胞耗竭对同种异体效应的T细胞库，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纤维化的分子基础。研究概念2将涉及鉴定患有抗体介导的损伤（高PRA）高风险的心脏移植候选者，并进行试验研究，以确定使用B细胞耗竭（Rituximab）（Rituximab），IVIG静脉曲张的组合，确定脱敏的安全性和功效。该研究将测试脱敏的假设将降低PRA，减少等待时间到心脏移植，并导致可接受的1年移植生存和功能。将在一个强大的北美心脏移植中心的强大财团内招募患者，该联盟是为正在进行的心脏移植CTOT05研究而开发的。相关的机理研究将决定脱敏方案如何影响预先形成的同种异体T和B细胞免疫，并将检验以下假设：残留的B和T细胞免疫记忆对供体抗原的反应性介导移植后同种异体移植后损伤。拟议的研究将解决肾脏和心脏移植方面的临床相关问题，无论结果如何，都将提供新的信息。 相关性：肾脏移植和心脏移植是器官衰竭的救生治疗方法，但移植器官并不能无限期持续。拟议工作的目标是1）测试改善移植结果的新方法（使器官持续更长的时间），2）确定可修改的风险因素以改善结果，3）确定为什么心脏或肾脏移植失败以设计更好的治疗方法。