Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

稳定儿童肝移植受者的免疫抑制撤药

• 批准号: 8704875
• 负责人: Sandy Feng
• 金额: $ 185.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-27 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704875
• 关键词: Address; Age; Allografting; Anti-Inflammatory Agents; Anti-inflammatory; Biological Markers; Childhood; Chronic; Clinical; Clinical Trials; Conduct Clinical Trials; Confidence Intervals; Consensus; Deterioration; Disease; Dose; Ensure; Fingerprint; Gene Expression Profile; General Population; Goals; Grant; Histologic; Histology; Immune; Immune Tolerance; Immunologics; Immunology; Immunosuppression; Incidence; Intervention Studies; Knowledge; Lead; Liver; Longitudinal Studies; Mediating; Medical; Mission; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; Organ Transplantation; Outcome; Outcome Measure; Outcome Study; Participant; Pathology; Patients; Population Control; Randomized; Refractory; Research; Risk; Safety; Solid; Specificity; Testing; Tissues; Transplant Recipients; Transplantation; Uncertainty; United States National Institutes of Health; Withdrawal; Work; arm; base; clinical decision-making; clinical phenotype; clinical practice; design; fundamental research; improved; innovation; liver biopsy; liver transplantation; mortality; peripheral blood; prevent; prospective; success; symposium; translational study

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.

描述（由申请人提供）：我们的长期目标是通过发现指导临床决策来改善儿科肝移植受者的结果 一般的免疫抑制管理和具体的免疫抑制最小化和/或戒断。 2007 年，美国国立卫生研究院 (NIH) 主办的关于儿科肝移植长期结果的共识会议得出结论：(1) 长期免疫抑制会引发大量非免疫和免疫相关并发症，(2) 识别可告知肝移植免疫机制的生物标志物。耐受性会降低并发症的风险，并导致个体化、最小化和/或退出的干预研究 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，评估包括耐受性、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，并探索作用机制”为了直接应对共识会议和 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，以检验特定儿童肝移植受者亚群能够安全、可靠地进行的假设。持久地退出主要终点是操作耐受的参与者的比例，定义为在最后一次免疫抑制剂量后 12 个月通过肝活检和肝脏测试评估成功退出免疫抑制并保持正常同种异体移植状态的参与者的比例。我们将开展广泛的转化研究，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（目标2) 当前的研究提供了一种创新且全面的方法，汇集了临床专家、移植病理学领域的领导者和移植免疫学领域的领导者，以解决知识方面的关键差距。该研究的预期结果将是确定操作耐受性的临床表型，这将使​​我们能够得出并验证交叉 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，并在此过程中显着改变稳定儿科肝移植的长期免疫抑制管理。