B7 Costimulatory Blockade in Pediatric Transplantation

描述(由申请人提供)：肾移植被广泛认为是终末期肾病儿童的首选治疗方法。最近的报道表明，儿童肾移植的效果很好，但在短期内取得良好效果的成功是不完美的，而且是短暂的，因为患者必须终生维持长期的免疫抑制。药物副作用、依从性和慢性排斥反应仍然是这类患者的主要临床问题。因此，旨在诱导供者特异性低反应耐受性的策略，在没有或最小限度长期免疫抑制的情况下，将对儿童产生独特的有益效果。最近我们对同种异体移植排斥反应的细胞和分子机制的了解取得了进展，这导致了在实验动物模型中开发新的策略来促进同种异体移植物的长期存活和诱导供者特异性耐受。其中一种有效的策略是阻断T细胞共刺激的B7途径。在成人移植受者中，最近的临床数据证实了CTLA4Ig LEA29Y在预防成人肾移植受者急性排斥反应方面的安全性和有效性。CTLA4Ig LEA29Y是一种阻断B7共刺激途径的融合蛋白。该应用的总体目标是研究B7受体阻滞剂在儿童肾移植受者中的免疫调节功能和机制。具体地说，我们计划进行以下研究：1.确定CTLA4Ig在儿童初次肾移植受者中的安全性并研究其免疫调节功能。我们的假设是，阻断B7将防止急性排斥反应，并允许在这一患者群体中节省钙调神经磷酸酶抑制剂和皮质类固醇。2.研究CTLA4Ig联合供体特异性输血和T细胞共刺激阻断对儿童亲缘关系移植受者的免疫调节作用。我们的假设是，供体同种异体抗原联合T细胞共刺激阻断可能导致供体特异性低反应状态的诱导，并将提供进一步减轻慢性免疫抑制的机会。3.我们计划使用新的免疫学方法，包括外周和移植物内监测激活和效应功能标志物的表达模式，以研究CTLA4Ig在人类中的作用机制。我们的假设是，阻断B7与抑制T细胞活化和同种异体移植排斥反应的效应机制有关。上述研究将有助于规划针对儿科移植受者的进一步的“耐受性”临床试验。

DESCRIPTION (provided by applicant): Renal transplantation is widely recognized as the treatment of choice for children with End Stage Renal Disease. Recent reports show that children have excellent outcomes of kidney transplantation, but the success in achieving excellent short-term results is imperfect and short-lived since patients have to be maintained on long-term immunosuppression for life. Drug side effects, compliance and chronic rejection continue to be major clinical problems in this patient population. Therefore, strategies designed to induce donor specific hypo-responsiveness tolerance with no or minimal long-term immunosuppression will have unique beneficial effects for children. Recent advances in our understanding of the cellular and molecular mechanisms of allograft rejection have lead to development of novel strategies to promote long-term allograft survival and induce donor specific tolerance in experimental animal models. One such effective strategy involves blocking the B7 pathway of T cell costimulation. Recent clinical data in adult transplant recipients established the safety and efficacy of CTLA4Ig LEA29Y, a fusion protein that blocks B7 costimulatory pathway, in preventing acute rejection in adult renal transplant recipients. The overall goal of this application is to study the immunomodulatory functions and mechanisms of B7 blockade in pediatric renal transplant recipients. Specifically, we plan to study the following: 1. Determine the safety and study the immunomodulatory functions of CTLA4Ig in pediatric primary renal transplant recipients. Our hypothesis is that B7 blockade will prevent acute rejection and allows sparing of calcineurin inhibitors and corticosteroids in this patient population. 2. Study the immunomodulatory functions of combining donor specific transfusion and T cell costimulatory blockade with CTLA4Ig in pediatric primary living related transplant recipients. Our hypothesis is that the administration of donor alloantigen with T cell costimulatory blockade may result in induction of a donor specific hyporesponsive state and will provide the opportunity to decrease chronic immunosuppression further. 3. We plan to use novel immunological assays including peripheral and intragraft monitoring for expression patterns of activation and effector function markers to study the mechanisms of CTLA4Ig in humans. Our hypothesis is that B7 blockade is associated with inhibition of T cell activation and the effector's mechanisms of allograft rejection. The above studies will help to plan further "tolerance" aimed clinical trials in pediatric transplant recipients.