Novel Therapies for Chronic Renal Allograft Dysfunction in Children

描述（由申请人提供）：本提案的主要假设是，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同种异体免疫反应中起关键作用，负责慢性同种异体移植排斥反应的开始和进展。由此推论，通过T细胞共刺激阻断或蛋白激酶C抑制来抑制T细胞的激活将阻止移植后慢性器官功能障碍的进展。第二个假设是，钙调磷酸酶抑制剂（CNI）由于其肾毒性在促进慢性同种异体移植物功能障碍中起重要作用。因此，去除CNIs，同时提供充分、安全、无毒的免疫抑制来抑制T细胞活化，可以防止器官功能障碍的进展，改善肾功能和长期预后。本提案的总体目标是开发预防和阻断儿童慢性同种异体移植物功能障碍进展的新疗法。我们已经组建了一个由6个大型儿童肾移植项目组成的联盟，这些项目都有参与创新免疫抑制方案的多中心协作随机临床试验的良好记录。我们还组建了五个机制核心实验室来定义慢性同种异体移植物功能障碍的生物标志物和新的治疗干预措施的效果。1 . Belatacept方案：在该方案中，我们将验证Belatacept阻断B7将阻断正在进行的同种免疫反应，并允许儿童肾移植受者从CNI转化，从而预防慢性同种异体移植功能障碍的进展和肾功能的改善。在与BMS的合作中，我们现在建议在移植后6-24个月开始使用belatacil，以消除CNI并防止儿童肾移植受者慢性同种异体移植物功能障碍的进展。由于belatacept以每月一次静脉输注的方式提供，该方案具有改善青少年移植中免疫抑制依从性的附加潜力。2 AEB071方案：在本方案中，我们将验证蛋白激酶C抑制将有效阻断正在进行的同种异体免疫反应并允许儿科肾移植受者退出CNI的假设，从而预防慢性同种异体移植功能障碍的进展和肾功能的改善。通过与诺华公司的合作，我们现在建议在儿童肾移植受者移植后6-24个月启动AEB071，以解除CNI并预防慢性同种异体移植物功能障碍的进展。3机制研究：我们将验证这样一个假设，即通过belatacept或AEB071抑制T细胞活化将抑制慢性同种异体移植排斥反应的效应机制，包括T细胞的同种异体反应性、同种异体抗体（B细胞）的产生，以及其他慢性炎症反应的介质。这些作用可以通过敏感和特异性的检测来检测，包括外周细胞/体液检测、外周血和植入物分子检测。这些研究的主要目的是了解belatacept/AEB071的作用机制，并开发一套替代生物标志物，用于儿科肾移植受者的慢性同种异体移植物功能障碍和稳定性。

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.