Novel Therapies for Chronic Renal Allograft Dysfunction in Children

描述(申请人提供)：这项建议的主要假设是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着关键作用，该反应负责慢性同种异体移植排斥反应的启动和进展。推论认为，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，可以防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，在促进慢性移植物功能障碍中起着重要作用。因此，去除CNI，加上提供足够、安全和无毒的免疫抑制药物来抑制T细胞的激活，应该可以防止器官功能障碍的进展，改善肾功能和长期预后。这项建议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。我们已经组成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有良好的记录。我们还组建了五个机械性核心实验室，以确定慢性同种异体移植功能障碍的生物标记物和新的治疗干预措施的效果。我们提出了两个替代试验：1belatacept方案：在这个方案中，我们将测试这样一个假设，即belatacept阻断B7将阻止正在进行的同种异体免疫反应，并允许儿童肾移植受者从CNI转化为CNI，从而防止慢性同种异体移植功能障碍的进展和改善肾功能。在与BMS的合作中，我们现在建议在移植后6-24个月开始应用贝拉塔普，以停用CNI，并防止儿童肾移植受者慢性移植物功能障碍的进展。由于贝拉西普是每月一次的静脉输液，该方案具有改善青少年移植免疫抑制依从性的额外潜力。2 AEB071方案：在这项方案中，我们将检验这样一个假设，即抑制蛋白激酶C将有效地阻断正在进行的同种异体免疫反应，并允许儿童肾移植受者停用CNI，从而防止慢性同种异体移植功能障碍的进展和改善肾功能。在与诺华公司的合作下，我们现在建议在移植后6-24个月启动AEB071，以停用CNI，并防止儿童肾移植受者慢性移植功能障碍的进展。3机制研究：我们将验证这样的假设，即贝拉塔塞普或AEB071抑制T细胞激活将抑制慢性同种异体移植排斥反应的效应机制，包括T细胞同种异体反应性、同种异体抗体产生(B细胞)以及慢性炎症反应的其他介质。这些影响可以通过敏感和特异的分析来检测，包括外周细胞/体液分析、外周血和移植物内分子分析。这些研究的主要目的是了解belatacept/AEB071的作用机制，并开发一套反映儿童肾移植受者慢性同种移植功能障碍和稳定性的替代生物标志物。

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.