Advancing Transplantation Outcomes in Children

项目摘要/摘要 肾移植被广泛认为是终末期肾病儿童的首选治疗方法。 疾病(ESRD)。预期寿命的好处是显著的，功能正常的肾脏移植能够 让孩子们长得好，发育几乎正常，提高他们在学校的学习成绩水平。 然而，目前的数据表明，几乎所有儿科受者的移植最终都会因为慢性疾病而失败。 同种异体移植物功能障碍，因此，保存长期同种异体移植物功能的目标是 未来的进步。此外，登记数据表明，机会性感染现在是最常见的 儿科人群中住院和死亡的原因。人们对病原体的特异性知之甚少 全程接触多种新病原体的儿科受者的保护性免疫 在没有TMemory的情况下的移植后时期。我们在这次试验中的方法是基于这样的概念 成功地保存同种异体移植物的长期功能需要一种免疫抑制方案， 靶向供体特异性同种异体抗体(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、识别和防止沉默的亚临床 移植物内炎症/排斥反应，这在移植后早期很常见。基于一个 最近一项联合mTOR抑制剂(MTORi)的先导性研究 儿科受试者，我们将检验早期引入贝拉坦/西罗莫司维持的假设 免疫抑制方案对儿童加强免疫调节、预防DSA安全有效 生产和增强长期同种异体移植的功能。EBV血清阳性的原发肾移植受者， 年龄在6岁到21岁之间的11个经验丰富的儿科临床中心将随机接受 抗胸腺细胞球蛋白诱导治疗和贝拉西普联合西罗莫司或 继续使用他克莫司和霉酚酸酯进行标准免疫抑制治疗。主要 终点分析包括重新开发DSA和36个月后评估同种异体移植的功能 跟进的问题。相关研究包括使用一种新的自动护理点尿液进行监测 生物标记物分析，以及病原体特异性免疫和细胞基础的深入机制研究 疫苗功能性抗体反应的评价。广泛的机械学研究也将是 评估贝拉泰塞/mTORi对细胞和体液同种免疫的影响，并进一步 尿液生物标记物的开发用于区分亚临床排斥反应和感染。有重要的 具有独特病原体特异性和同种异体免疫反应的儿科受者未满足的临床需求 在移植后。总体而言，这项建议的相关性在于，它建立在以前试验的基础上，以测试 一种新的药物(Belatacept)针对同种异体移植功能障碍；深入的机械监测将使 预测患者的病程，我们的发现将适用于其他实体器官移植的接受者。

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.