Novel Therapies of Chronic Allograft Dysfunction

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。虽然同种异体移植的短期存活率一直在稳步提高，但长期存活率仍然不是最理想的。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排斥反应。这个应用程序基于两个主要假设。第一个假说是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异体免疫反应中起着关键作用，该反应负责慢性同种异体移植排斥反应的启动和进展。推论是，通过T细胞共刺激阻断来抑制T细胞的激活，应该可以防止移植后慢性器官功能障碍的进展。第二种假说认为，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起着重要作用。因此，对于移植后早期产生新的抗人类白细胞抗原同种异体抗体的移植受者，靶向B细胞和抑制进一步的同种异体抗体的产生应该可以防止器官功能障碍的进展，改善长期结果。这项应用的总体目标是开发新的治疗方法来预防和阻止慢性移植物功能障碍的进展。根据CTOT-RFA的要求，我们将提议在哈佛大学移植中心和加州大学旧金山分校移植项目之间建立一个联盟，以测试两种不同的方法：第一种是多器官移植方法，第二种是器官特异性方法。在多器官方案中，我们将检验这样一个假设，即B7共刺激阻断(与LEA29Y一起)将阻止正在进行的同种免疫反应，并允许肾和心脏移植受者停用钙调神经磷酸酶抑制剂，从而防止慢性同种异体移植功能障碍的进展和改善肾功能。在器官特异性方案中，我们将检验这样的假设，即在早期产生新生抗人类白细胞抗原同种异体抗体的肾移植受者中，抗CD20(利妥昔单抗)耗尽B细胞将导致抗体产生抑制，体液排斥反应减轻，肾移植功能和慢性移植物肾病的病理改变得到改善。所有三项试验都将伴随着广泛的机制研究，包括敏感和特异的分析，包括外周细胞/体液分析和移植物内分子分析，以检测同种免疫激活和效应功能标记的表达模式。这些研究的主要目的是了解B7阻断和B细胞耗竭在体内的作用机制，并开发一套器官移植受者慢性同种异体排斥反应的替代标志物。

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.