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: 8332618
• 负责人: Sandy Feng
• 金额: $ 198.53万
• 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/8332618
• 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. PUBLIC HEALTH RELEVANCE: The objectives of the application are to assess the efficacy of immunosuppression withdrawal for stable pediatric liver transplant recipients and to identify a cross-platform biomarker predictive of operational tolerance. The knowledge gained will redefine clinical practice, freeing targeted patients from the morbidity associated with chronic, lifelong immunosuppression.

描述（由申请人提供）：我们的长期目标是改善具有发现的儿科肝移植接受者的结果，以指导与 特定于免疫抑制管理和免疫抑制最小化和/或戒断。 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 免疫抑制。共识会议的结论与移植免疫学方面的NIAID使命非常吻合，以“进行临床试验，以评估包括公差，抗炎和免疫调节性策略，以评估方法，以治疗和防止免疫介导的疾病和防止免疫介导的疾病，并探索这种挑战的动作机制。多中心，单臂，前瞻性，纵向研究，以测试一个假说，即儿科肝移植受者的定义子集可以安全，持久地退出免疫抑制（AIM 1）（AIM 1）将是从操作中撤离的人，并将其定义为依从率和依从性，并维持了依从率依从于免疫范围。最后一次免疫抑制剂量后的几个月。该研究的预期结果将是鉴定操作耐受性的临床表型，这将使​​我们能够得出和验证十字架 平台 - 临床，组织学，转录和/或免疫学 - 生物标志物可预测操作耐受性，并在此过程中大大改变了稳定的儿科肝移植的长期免疫抑制管理。 公共卫生相关性：该应用程序的目标是评估免疫抑制戒断对稳定的儿科肝移植接受者的功效，并确定跨平台生物标志物的操作耐受性预测。获得的知识将重新定义临床实践，使目标患者摆脱与慢性，终身免疫抑制有关的发病率。