B7 Costimulatory Blockade in Pediatric Transplantation

B7 儿科移植中的共刺激阻断

• 批准号: 6795138
• 负责人: WILLIAM E. HARMON
• 金额: $ 137.22万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6795138
• 关键词: CD28 molecule; MHC class I antigen; adolescence (12-20); artificial immunosuppression; calcineurin; child (0-11); clinical research; cooperative study; human subject; immune tolerance /unresponsiveness; immunomodulators; kidney transplantation; pediatrics; sirolimus; surface antigens; transplant rejection; transplantation immunology

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.

描述（由申请人提供）：肾移植被广泛认为是患有终末期肾病的儿童的首选治疗方法。最近的报告表明，儿童肾移植获得了良好的结果，但取得良好的短期结果的成功是不完美且短暂的，因为患者必须终生维持长期免疫抑制。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无需或最小程度长期免疫抑制的策略将对儿童产生独特的有益效果。我们对同种异体移植排斥的细胞和分子机制的理解的最新进展导致了新策略的发展，以促进长期同种异体移植存活并在实验动物模型中诱导供体特异性耐受。其中一种有效策略涉及阻断 T 细胞共刺激的 B7 途径。成人移植受者的最新临床数据证实了 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方面的安全性和有效性。本申请的总体目标是研究 B7 阻断在儿童肾移植受者中的免疫调节功能和机制。具体来说，我们计划研究以下内容： 1.确定CTLA4Ig在儿童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神经磷酸酶抑制剂和皮质类固醇。 2. 研究供者特异性输血和T细胞共刺激阻断联合CTLA4Ig对儿童原代活体相关移植受者的免疫调节功能。我们的假设是，给予供体同种抗原和 T 细胞共刺激阻断可能会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，包括外周和移植物内激活和效应功能标记物表达模式的监测，来研究CTLA4Ig在人类中的机制。我们的假设是 B7 阻断与 T 细胞激活的抑制和同种异体移植排斥的效应机制有关。上述研究将有助于计划进一步针对儿科移植受者的“耐受性”临床试验。