Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

描述（由申请人提供）：我们的长期目标是改善儿科肝移植受者的结局，并通过发现来指导与以下相关的临床决策： 一般的免疫抑制管理和具体的免疫抑制最小化和/或撤销。2007年，NIH主办的关于儿科肝移植长期结局的共识会议得出结论：（1）长期免疫抑制会导致大量非免疫和免疫相关并发症，（2）识别生物标志物，告知免疫耐受机制，将降低并发症的风险，并导致干预研究个体化，最小化和/或退出 免疫抑制共识会议的结论与NIAID在移植免疫学方面的使命高度一致，即"进行临床试验，以评估包括致耐受性、抗炎和免疫调节策略在内的方法，以治疗和预防免疫介导的疾病，并探索这些方法的作用机制。为了直接解决共识会议和NIAID提出的挑战，我们将进行一项多中心、单臂、前瞻性、纵向研究，以检验一个确定的儿科肝移植受者子集可以安全持久地退出免疫抑制的假设（目标1）。主要终点将是手术耐受的受试者比例，定义为在末次免疫抑制剂给药后12个月通过肝活检和肝脏检查评估成功退出免疫抑制并维持正常同种异体移植状态的受试者。我们将进行一系列广泛的转化研究，吸引免疫耐受网络内外的研究团队，其目标是识别和验证预测操作耐受性的跨平台生物标志物（Aim 2）当前的研究提供了一种创新和全面的方法，汇集了临床专家，移植病理学的领导者和移植免疫学的领导者，以解决知识的关键差距。这项研究的预期结果将是确定一个临床表型的操作耐受性，这将使我们能够推导和验证一个交叉 平台-临床、组织学、转录和/或免疫学-预测操作耐受性的生物标志物，并且在这样做时，实质上改变了稳定的儿科肝移植的长期免疫抑制管理。

DESCRIPTION (provided by applicant): Our long-term objective is to improve outcomes for pediatric liver transplant recipients with discoveries to guide clinical decision-making related to immunosuppression management in general and immunosuppression minimization and/or withdrawal in specific. In 2007, an NIH-sponsored consensus conference on long-term outcomes in pediatric liver transplantation concluded that (1) long-term immunosuppression precipitates substantial non-immune and immune-related complications and that (2) identification of biomarkers that inform immunologic mechanisms of tolerance would lessen the risk for complications and lead to intervention studies to individualize, minimize, and/or withdraw immunosuppression. The conclusion of the consensus conference is strongly aligned with the NIAID mission in transplant immunology to "conduct clinical trials to evaluate approaches that include tolerogenic, anti-inflammatory, and immunomodulatory strategies to treat and prevent immune-mediated diseases and to explore the mechanisms of action of such approaches. To directly address the challenges put forth at the consensus conference and by NIAID, we will conduct a multi-center, single arm, prospective, longitudinal study to test the hypothesis that a defined subset of pediatric liver transplant recipients can safely and durably withdraw from immunosuppression (Aim 1). The primary endpoint will be the proportion of participants who are operationally tolerant, defined as those who successfully withdraw from immunosuppression and maintain normal allograft status, assessed by liver biopsy and liver tests, 12 months after the last immunosuppression dose. We will conduct an extensive battery of translational studies, engaging research teams within and outside the Immune Tolerance Network, the goal of which is to identify and validate a cross- platform biomarker predictive of operational tolerance (Aim 2) The current study provides an innovative and comprehensive approach, bringing together clinical experts, leaders in transplant pathology and leaders in transplant immunology to address critical gaps in knowledge. The expected outcome of the study will be the identification of a clinical phenotype of operational tolerance that will enable us to derive and validate a cross platform - clinical, histological, transcriptional, and/or immunologic - biomarker predictive of operational tolerance, and in doing so, substantially alter the long-term immunosuppression management of stable pediatric liver transplantation.