Novel Therapies of Chronic Allograft Dysfunction

慢性同种异体移植功能障碍的新疗法

• 批准号: 7869850
• 负责人: Mohamed H Sayegh
• 金额: $ 214.48万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7869850
• 关键词: Academic Medical Centers; Acute; Address; Adult; Alloantigen; Allografting; Animals; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Biological Assay; Biopsy; Brain Death; Bronchioles; CD4 Positive T Lymphocytes; CD40 Ligand; Calcineurin inhibitor; California; Cardiac; Cell Aging; Cells; Cellular Infiltration; Characteristics; Charge; Chimeric Proteins; Chronic; Chronic rejection of renal transplant; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical Trials Design; Complex; Cytomegalovirus; Data; Delayed Hypersensitivity; Development; Duct (organ) structure; Effector Cell; Event; Experimental Animal Model; Experimental Models; Failure; Fibroblasts; Fibrosis; Functional disorder; General Hospitals; Goals; Graft Survival; Hand; Heart; Heart Transplantation; Hospitals; Human; Hyperlipidemia; Hypertension; Immune response; Immunoglobulin G; Immunosuppression; Immunosuppressive Agents; In Vitro; Infection; Inflammatory Response; Injury; Interruption; Isoantibodies; Israel; Kidney; Kidney Transplantation; LEA29Y; Lead; Letters; Life; Link; Liver; Lung; MS4A1 gene; Macrophage Activation; Massachusetts; Mediating; Mediator of activation protein; Modeling; Molecular; Monoclonal Antibodies; Mononuclear; Natural History; Operative Surgical Procedures; Organ; Organ Transplantation; Outcome; Pancreas; Pathogenesis; Pathway interactions; Patients; Pattern; Peptides; Peripheral; Pharmaceutical Preparations; Phase; Play; Population; Prevention; Prevention therapy; Primates; Procedures; Process; Production; Protocols documentation; Publications; Randomized Clinical Trials; Registries; Renal function; Reperfusion Injury; Research; Research Personnel; Role; Safety; San Francisco; Secondary to; Signal Transduction; Smooth Muscle Myocytes; Solid; Structure; Surrogate Markers; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TNFSF5 gene; Techniques; Testing; Toxic effect; Transplant Recipients; Transplantation; Universities; Vascular Diseases; Withdrawal; Woman; Work; attenuation; base; clinical application; end-stage organ failure; experience; improved; improved functioning; in vivo; interstitial; kidney allograft; knockout gene; monocyte; mutant; nephrotoxicity; novel; prevent; programs; response; rituximab; success

DESCRIPTION (provided by applicant): Transplantation is widely recognized as the treatment of choice for end stage organ failure. While short-term allograft survival has been steadily improving, long-term survival is still not optimal. Most grafts will eventually cease to function, primarily due to chronic allograft rejection. This application is based on two primary hypotheses. The first hypothesis is that T cell recognition of alloantigen, costimulation and subsequent activation plays a critical role in orchestrating the alloimmune response responsible for initiation and progression of chronic allograft rejection. The corollary hypothesis is that inhibiting T cell activation by T cell costimulatory blockade should prevent progression of chronic organ dysfunction following transplantation. The second hypothesis is that humoral immune responses play an important role in promoting chronic rejection and subsequent graft dysfunction. Therefore, targeting B cells and inhibition of further alloantibody production in transplant recipients who develop de novo anti-HLA alloantibodies early after transplantation should prevent the progression of organ dysfunction and improve long-term outcome. The overall goal of this application is to develop novel therapies for prevention and interruption of progression of chronic allograft dysfunction. As required by the CTOT-RFA we will propose to establish a consortium between the Harvard Transplant Centers and the University of California San Francisco Transplant Program to test two different approaches: the first one is a multi-organ approach and the second is an organ-specific one. In the multi-organ protocol we will test the hypothesis that B7 costimulation blockade (with LEA29Y) will block ongoing alloimmune responses and allow withdrawal of calcineurin inhibitors in renal and cardiac transplant recipients leading to prevention of progression of chronic allograft dysfunction and improvement in renal function. In the organ-specific protocol we will test the hypothesis that B cell depletion by anti-CD20 (Rituximab) in renal allograft recipients who develop early de novo anti-HLA alloantibodies will result in inhibition of antibody production, attenuation of humoral rejection and improvement of renal transplant function and pathological changes of chronic allograft nephropathy. All three trials will be accompanied by extensive mechanistic studies involving sensitive and specific assays, including peripheral cellular/humoral assays and intragraft molecular assays for expression patterns of alloimmune activation and effector function markers. The main goal of these studies is to understand the mechanisms of action of B7 blockade and B cell depletion in vivo, and to develop a set of surrogate markers of chronic allograft rejection in organ transplant recipients.

描述（申请人提供）：移植被广泛认为是终端器官衰竭选择的治疗方法。尽管短期同种异体移植的存活率一直在稳步改善，但长期生存仍然不是最佳的。大多数移植物最终将不再起作用，这主要是由于慢性同种异体移植排斥。该应用基于两个主要假设。第一个假设是，T细胞对同种抗原，共刺激和随后的激活的识别在策划负责慢性同种异体移植排斥反应的引发和进展的同种异体免疫反应中起着至关重要的作用。推论假设是，通过T细胞抑制T细胞的抑制T细胞激活应防止移植后慢性器官功能障碍的进展。第二个假设是体液免疫反应在促进慢性排斥和随后的移植功能障碍中起重要作用。因此，靶向B细胞并抑制移植后早期抗HLA同种抗体的移植受者中进一步的同种抗体产生，应防止器官功能障碍的发展并改善长期结果。该应用的总体目标是开发用于预防和中断慢性同种异体功能障碍进展的新型疗法。根据CTOT-RFA的要求，我们将建议在哈佛移植中心和加利福尼亚大学旧金山移植计划之间建立一个财团，以测试两种不同的方法：第一种方法是多器官方法，第二种方法是特定于器官特定的方法。在多器官方案中，我们将测试以下假设：B7共刺激阻滞（与LEA29Y）将阻止正在进行的同种免疫性反应，并允许在肾脏和心脏移植受体中撤回钙调神经蛋白抑制剂，从而预防慢性同种异体移植功能和改善肾脏功能的进展。在器官特异性方案中，我们将检验以下假设：抗CD20（利妥昔单抗）在同种异体移植受体中造成B细胞的耗竭，这些受体在肾脏移植的受体中，这些受体发展为新早期的抗HLA同抗体，会导致抗体产生，衰减，对肾移植功能和病理学变化的肾脏抑制和改善，使其抑制。这三个试验将伴随着涉及敏感和特定测定法的广泛机械研究，包括外周血细胞/体液测定和分类内分子测定法，用于同种免疫激活和效应子功能标记的表达模式。这些研究的主要目的是了解体内B7封锁和B细胞耗竭的作用机理，并在器官移植受者中开发一组慢性同种异体移植排斥反应的替代标记。