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治疗选择。最近的报告显示，儿童肾移植有很好的结果，但短期效果的成功是不完美的和短暂的，因为患者必须终身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该患者群体的主要临床问题。因此，旨在诱导供体特异性低反应性耐受而没有或只有很小的长期免疫抑制的策略将对儿童产生独特的有益影响。近年来，我们对同种异体移植排斥反应的细胞和分子机制的理解取得了新的进展，从而在实验动物模型中开发了促进同种异体移植长期存活和诱导供体特异性耐受的新策略。其中一个有效的策略是阻断T细胞共刺激的B7通路。近期成人肾移植受者的临床数据证实了CTLA4Ig LEA29Y（一种阻断B7共刺激途径的融合蛋白）在预防成人肾移植受者急性排斥反应中的安全性和有效性。本应用程序的总体目标是研究B7阻断在儿童肾移植受者中的免疫调节功能和机制。具体而言，我们计划研究以下内容：1。确定CTLA4Ig在小儿原发性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B7阻断将防止急性排斥反应，并允许在该患者群体中保留钙调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原发性活体移植受者的免疫调节作用。我们的假设是，供体同种异体抗原与T细胞共刺激阻断可能导致诱导供体特异性低反应状态，并将提供进一步减少慢性免疫抑制的机会。3. 我们计划使用新的免疫学检测方法，包括外周和植入物内监测激活和效应功能标记物的表达模式，以研究人类CTLA4Ig的机制。我们的假设是B7阻断与T细胞活化的抑制和同种异体移植排斥反应的效应机制有关。上述研究将有助于计划进一步针对儿童移植受者的“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.