Advancing Transplantation Outcomes in Children

项目总结/摘要 肾移植被广泛认为是治疗儿童终末期肾病的首选方法。 疾病（ESRD）。预期寿命的好处是显着的，一个功能正常的肾移植， 儿童健康成长，发育几乎正常，提高他们的学校教育水平。 然而，目前的数据表明，几乎所有的移植在儿科受体最终将失败，由于慢性炎症， 同种异体移植物功能障碍，因此，保持长期同种异体移植物功能的目标是关键领域， 未来的进展。此外，登记数据表明，机会性感染现在是最常见的 儿科人群住院和死亡的原因。关于病原体特异性 保护性免疫力的儿科受者谁暴露于多种新型传染性病原体在整个 移植后在缺乏T记忆的情况下。我们在这个试验中的方法是基于这样的概念 移植物长期功能的成功保存需要免疫抑制方案， 靶向供体特异性同种抗体（DSA）的产生，同时保留病原体特异性免疫。我们也 建议儿科接受者需要精确的工具来监测，识别和预防沉默的亚临床 移植物内炎症/排斥反应，这在移植后早期很常见。基于 最近的一项初步研究使用贝拉西普治疗与mTOR抑制剂（mTORi）联合治疗 在儿科受试者中，我们将检验早期引入贝拉西普/西罗莫司维持治疗的假设， 免疫抑制方案是安全有效，可增强免疫调节，预防DSA 生产和增强长期同种异体移植功能。EBV血清阳性的初次肾移植受者， 来自11家经验丰富的儿科临床中心的6 - 21岁儿童将随机接受 用抗胸腺细胞球蛋白进行诱导治疗，贝拉西普治疗与西罗莫司联合，或 继续使用他克莫司和吗替麦考酚酯进行标准免疫抑制治疗。初级 终点分析包括36个月后的新发DSA发展和同种异体移植物功能评估 的后续行动。相关研究包括使用新型自动化护理点尿液监测 生物标志物测定，以及病原体特异性免疫的细胞基础上的深入机制研究， 评价对疫苗的功能性抗体应答。还将进行广泛的机械研究。 进行评估贝拉西普/mTORi对细胞和体液同种免疫的影响，并进一步评估贝拉西普/mTORi对细胞和体液同种免疫的影响。 发展尿生物标志物以区分亚临床排斥和感染。存在显著 具有独特病原体特异性和同种免疫应答的儿科受者的未满足临床需求 移植后。总的来说，这项建议的相关性在于，它建立在以前的试验基础上，以测试 一种新的药物（贝拉西普）靶向同种异体移植物功能障碍;深入的机制监测将允许 我们的研究结果将适用于其他实体器官移植的受者。

Project Summary/Abstract Renal transplantation is widely recognized as the treatment of choice for children with end stage renal disease (ESRD). The life expectancy benefit is significant and a functioning renal transplant enables children to grow well, develop almost normally and improve their school educational performance levels. However, current data indicate that virtually all grafts in pediatric recipients will eventually fail due to chronic allograft dysfunction, and as such, the goal of preserving long-term allograft function is the key area for future progress. Furthermore, registry data indicate that opportunistic infections are now the most common cause for hospitalization and death in the pediatric population. Little is known about pathogen-specific protective immunity in pediatric recipients who are exposed to multiple novel infectious agents throughout the post-transplant period in the absence of Tmemory. Our approach in this trial is based on the concept that successful preservation of long-term allograft function requires an immunosuppressive regimen that targets donor specific alloantibody (DSA) production while preserving pathogen-specific immunity. We also propose that pediatric recipients require precision tools to monitor, identify and prevent silent subclinical intragraft inflammation/rejection, which is common at early times in the post transplant period. Based on a recent pilot study using de novo Belatacept therapy in combination with an mTOR inhibitor (mTORi) in pediatric recipients, we will test the hypothesis that early introduction of a Belatacept/sirolimus maintenance immunosuppressive regimen is safe and efficacious in children to augment immunoregulation, prevent DSA production and enhance long-term allograft function. EBV seropositive primary renal transplant recipients, aged between 6 and 21 yrs, from eleven experienced pediatric clinical centers will be randomized to receive induction therapy with anti-thymocyte globulin and either Belatacept therapy in combination with sirolimus or remain on standard immunosuppression therapy using tacrolimus and mycophenolate mofetil. Primary endpoint analysis includes de novo DSA development and assessment of allograft function after 36 months of follow up. Associated studies include surveillance monitoring using a novel automated point-of-care urine biomarker assay, and in-depth mechanistic studies on the cellular basis for pathogen-specific immunity and evaluation of functional antibody responses to vaccine. Extensive mechanistic studies will also be performed to assess the impact of Belatacept/mTORi on cellular and humoral alloimmunity and the further development of urinary biomarkers to differentiate subclinical rejection from infection. There are significant unmet clinical needs in pediatric recipients who have unique pathogen-specific and alloimmune responses following transplantation. Overall, the relevance of this proposal is that it builds upon previous trials to test if a novel agent (Belatacept) targets allograft dysfunction; in-depth mechanistic monitoring will allow for the prediction of patient course, and our findings will be applicable to recipients of other solid organ transplants.