Novel Therapies for Chronic Renal Allograft Dysfunction in Children

儿童慢性同种异体移植肾功能障碍的新疗法

• 批准号: 7906698
• 负责人: WILLIAM E. HARMON
• 金额: $ 90.46万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906698
• 关键词: Adherence; Adolescent; Adult; Alloantigen; Allografting; Area; B-Lymphocytes; Biological Assay; Biological Markers; Calcineurin inhibitor; Child; Childhood; Chronic; Collaborations; Functional disorder; Goals; Human; Immunosuppression; Inflammatory Response; Interruption; Intravenous infusion procedures; Investigation; Isoantibodies; Kidney Transplantation; Laboratories; Lead; Letters; Mediator of activation protein; Molecular; Organ; Outcome; Peripheral; Pharmacologic Substance; Phase II Clinical Trials; Phase III Clinical Trials; Play; Prevention; Prevention therapy; Production; Protein Kinase C; Protocols documentation; Randomized Clinical Trials; Recording of previous events; Records; Renal function; Role; Scientist; Surrogate Markers; T-Cell Activation; T-Lymphocyte; Testing; Time; Transplant Recipients; Transplantation; Withdrawal; allograft rejection; experience; improved; in vivo; innovation; kidney allograft; nephrotoxicity; novel; novel therapeutic intervention; peripheral blood; prevent; programs; response

DESCRIPTION (provided by applicant): The primary hypothesis of this proposal 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 or by Protein Kinase C inhibition will prevent progression of chronic organ dysfunction following transplantation. The secondary hypothesis is that calcineurin inhibitors (CNI) play an important role in promoting chronic allograft dysfunction because of their nephrotoxicity. Therefore, removing CNIs, along with provision of adequate, safe and non-toxic immunosuppression to inhibit T cell activation should prevent the progression of organ dysfunction, and improve renal function and long-term outcome. The overall goal of this proposal is to develop novel therapies for prevention and interruption of progression of chronic allograft dysfunction in children. We have formed a consortium of six large pediatric kidney transplant programs with proven track records of participation in multi-center collaborative randomized clinical trials of innovative immunosuppression protocols. We also have assembled five mechanistic core laboratories to define the biomarkers of chronic allograft dysfunction and the effects of novel therapeutic interventions. We are proposing two alternative trials: 1 Belatacept Protocol: In this protocol we will test the hypothesis that B7 blockade by belatacept will block ongoing alloimmune responses and allow conversion from CNI in pediatric renal transplant recipients leading to prevention of progression of chronic allograft dysfunction and improvement in renal function. In collaboration with BMS we now propose to initiate belatacept 6-24 months post-transplantation to withdraw CNI and prevent progression of chronic allograft dysfunction in pediatric kidney transplant recipients. Since belatacept is provided as once monthly intravenous infusions, the protocol has the added potential to improve immunosuppression adherence in adolescent transplant. 2 AEB071 Protocol: In this protocol, we will test the hypothesis that Protein Kinase C inhibition will effectively block ongoing alloimmune responses and permit CNI withdrawal in pediatric renal transplant recipients leading to prevention of progression of chronic allograft dysfunction and improvement in renal function. In collaboration with Novartis we now propose to initiate AEB071 6-24 months post-transplantation to withdraw CNI and prevent progression of chronic allograft dysfunction in pediatric kidney transplant recipients. 3 Mechanistic Studies: We will test the hypothesis that inhibition of T cell activation by belatacept or AEB071 will inhibit the effector mechanisms of chronic allograft rejection, including T cell alloreactivity, alloantibody production (B cells), as well as other mediators of the chronic inflammatory response. These effects can be detected by sensitive and specific assays, including peripheral cellular/humoral assays, and peripheral blood and intragraft molecular assays. The main goal of these studies is to understand the mechanisms of action of belatacept/AEB071 and to develop a set of surrogate biomarkers of chronic allograft dysfunction and stability in pediatric kidney transplant recipients.

描述（由申请人提供）：该提案的主要假设是，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负责慢性同种异体移植排斥的启动和进展的同种免疫反应中发挥着关键作用。推论假设是，通过 T 细胞共刺激阻断或蛋白激酶 C 抑制来抑制 T 细胞活化将阻止移植后慢性器官功能障碍的进展。第二个假设是钙调神经磷酸酶抑制剂（CNI）由于其肾毒性而在促进慢性同种异体移植物功能障碍中发挥重要作用。因此，去除 CNI，并提供充分、安全和无毒的免疫抑制来抑制 T 细胞活化，应该可以防止器官功能障碍的进展，并改善肾功能和长期结果。该提案的总体目标是开发新的疗法来预防和阻止儿童慢性同种异体移植功能障碍的进展。我们已经成立了一个由六个大型儿科肾移植项目组成的联盟，这些项目在参与创新免疫抑制方案的多中心协作随机临床试验方面拥有良好的记录。我们还组建了五个机械核心实验室来定义慢性同种异体移植功能障碍的生物标志物和新型治疗干预措施的效果。我们提出两项替代试验： 1 贝拉西普方案：在该方案中，我们将测试以下假设：贝拉西普阻断 B7 将阻断持续的同种免疫反应，并允许儿科肾移植受者从 CNI 转化，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。现在，我们与 BMS 合作，建议在移植后 6-24 个月启动 Belatacept，以撤回 CNI 并预防儿科肾移植受者慢性同种异体移植物功能障碍的进展。由于贝拉西普每月一次静脉输注，因此该方案具有提高青少年移植中免疫抑制依从性的额外潜力。 2 AEB071 方案：在本方案中，我们将测试蛋白激酶 C 抑制将有效阻断持续的同种免疫反应并允许儿科肾移植受者撤回 CNI 的假设，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。我们现在与诺华合作，建议在移植后 6-24 个月启动 AEB071，以撤回 CNI 并预防儿科肾移植受者慢性同种异体移植功能障碍的进展。 3 机制研究：我们将测试以下假设：belatacept 或 AEB071 抑制 T 细胞活化将抑制慢性同种异体移植排斥的效应机制，包括 T 细胞同种异体反应性、同种抗体产生（B 细胞）以及慢性炎症反应的其他介质。这些效应可以通过敏感且特异性的测定来检测，包括外周细胞/体液测定以及外周血和移植物内分子测定。这些研究的主要目标是了解 belatacept/AEB071 的作用机制，并开发一套儿童肾移植受者慢性同种异体移植功能障碍和稳定性的替代生物标志物。