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: 7279776
• 负责人: Mohamed H Sayegh
• 金额: $ 324.1万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7279776
• 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; Numbers; Operative Surgical Procedures; Organ; Organ Transplantation; Outcome; Pancreas; Pathogenesis; Pathway interactions; Patients; Pattern; Peptides; Peripheral; Personal Satisfaction; Pharmaceutical Preparations; Phase; Play; Population; Prevention; Prevention therapy; Primates; Procedures; Process; Production; Protocols documentation; Publications; Randomized; Rate; 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; Therapeutic immunosuppression; Toxic effect; Transplant Recipients; Transplantation; Universities; 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（由申请人提供）：移植被广泛认为是终末期器官衰竭的首选治疗方法。虽然同种异体移植物的短期存活率一直在稳步提高，但长期存活率仍不理想。大多数移植物最终将停止功能，主要是由于慢性同种异体移植物排斥。该应用基于两个主要假设。第一个假设是，T 细胞对同种异体抗原的识别、共刺激和随后的激活在协调同种免疫反应中发挥着关键作用，该反应负责慢性同种异体移植排斥的启动和进展。推论假设是，通过 T 细胞共刺激阻断来抑制 T 细胞活化，可以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反应和随后的移植物功能障碍中发挥重要作用。因此，在移植后早期从头产生抗 HLA 同种抗体的移植受者中，靶向 B 细胞并抑制进一步同种抗体的产生，应能防止器官功能障碍的进展并改善长期结果。该申请的总体目标是开发新的疗法来预防和阻止慢性同种异体移植功能障碍的进展。根据 CTOT-RFA 的要求，我们将提议在哈佛移植中心和加州大学旧金山分校移植计划之间建立一个联盟，以测试两种不同的方法：第一种是多器官方法，第二种是特定器官方法。在多器官方案中，我们将测试以下假设：B7 共刺激阻断（与 LEA29Y）将阻断持续的同种免疫反应，并允许肾和心脏移植受者撤回钙调神经磷酸酶抑制剂，从而预防慢性同种异体移植功能障碍的进展并改善肾功能。在器官特异性方案中，我们将测试以下假设：在早期产生抗HLA同种抗体的同种异体肾移植受者中，通过抗CD20（利妥昔单抗）消除B细胞将导致抗体产生的抑制、体液排斥的减弱以及肾移植功能和慢性同种异体移植肾病病理变化的改善。所有三项试验都将伴随着广泛的机制研究，涉及敏感和特异性测定，包括外周细胞/体液测定和移植物内分子测定，用于同种免疫激活和效应功能标记物的表达模式。这些研究的主要目标是了解体内 B7 阻断和 B 细胞耗竭的作用机制，并开发一套器官移植受者慢性同种异体移植排斥的替代标记。