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治疗选择。虽然移植物的短期存活率一直在稳步提高，但长期存活率仍然不是最佳的。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物排斥。本申请基于两个主要假设。第一个假设是T细胞识别同种异体抗原，共刺激和随后的激活在协调负责慢性同种异体移植排斥反应的启动和进展的同种异体免疫反应中起着关键作用。推论的假设是，通过T细胞共刺激阻断来抑制T细胞活化应该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应答在促进慢性排斥反应和随后的移植物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产生新生抗HLA同种抗体的移植受者进一步产生同种抗体，应可预防器官功能障碍的进展并改善长期结局。本申请的总体目标是开发用于预防和中断慢性同种异体移植物功能障碍进展的新疗法。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弗朗西斯科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，我们将检验以下假设：B7共刺激阻断（与LEA 29 Y）将阻断正在进行的同种免疫应答，并允许在肾和心脏移植受者中停用钙调磷酸酶抑制剂，从而预防慢性同种异体移植物功能障碍的进展并改善肾功能。在器官特异性方案中，我们将检验以下假设：在早期新发抗HLA同种异体抗体的肾移植受者中，抗CD 20（利妥昔单抗）清除B细胞将抑制抗体产生，减轻体液排斥反应，改善肾移植功能和慢性移植肾病的病理变化。所有三项试验将伴随广泛的机制研究，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志物的表达模式。这些研究的主要目的是了解体内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.