Adult to Adult LDLT Cohort Study

描述(由申请人提供)：A2ALL研究小组成立的目的是了解活体供体移植(LDLT)对供者的生理和心理社会影响，探索确保供体安全和结果的方法，研究受者的结果，并应用创新的机械方法更好地了解与此环境相关的肝脏再生和免疫生物学过程。来自A2ALL联盟的科学探索产生了重大贡献，促进了我们对该程序的理解，为捐赠者和接受者的选择建立了重要的指导方针，并为更明智的决定汇编了相关信息。这项申请的目的是展示我们对正在进行的A2ALL研究的承诺，描述确保收集预期数据的既定程序，这是A2ALL联盟的核心任务，并提出科学研究，以加强我们对对捐赠者和接受者的康复和长期福祉至关重要的生物反应的理解。我们的概念建议旨在研究影响供体和受体肝脏功能的再生分子途径以及LDLT受者的同种免疫反应模式。1.供体概念建议：这项建议将寻求确定供体肝脏残留物和外周血中恢复的分子模式，以指示和预测最终肝功能和质量的恢复。这将通过关联残叶和顺序外周血mRNA图谱中的基因表达，以及供体肝再生的纵向评估和定量肝功能测试来实现。2.接受者概念建议：采用随机临床试验设计，该建议将调查LDLT是否有助于安全地将免疫抑制降至最低。在一项平行的机制研究中，我们将调查外周血细胞mRNA图谱是否提供了一种预测和诊断LDLT同种异体移植排斥反应的非侵入性手段。这项建议中提出的目标可以在延长A2ALL的时间框架内实现，并利用现有的临床数据库、存储的可用于分子分析的供体和受者样本，并将已经登记参加A2ALL并符合条件并愿意参与免疫抑制最小化研究的受者纳入预期的介入研究。 与公共卫生相关：随着结果的改善和更多的益处得到承认，人们对活体供体移植的兴趣越来越大。在发生重大扩张之前，重要的是确定活体供体手术对供体福祉和受者结局的影响。改善供者肝功能和再生的潜在干预措施，以及努力延长受者的移植物功能并将免疫抑制的副作用降至最低，都可能对长期结果产生重大影响。

DESCRIPTION (provided by applicant): The A2ALL study group was established with the aim to understand the physiological and psychosocial impact of living donor transplantation (LDLT) on the donor, explore methods to assure donor safety and outcomes, to study outcomes in the recipient, and to apply innovative mechanistic methods to better understand the processes of liver regeneration and immunobiology that are pertinent to this setting. The scientific explorations from the A2ALL consortium have resulted in significant contributions that have advanced our understanding of the procedure, established important guidelines for donor and recipient selection, and compiled pertinent information for a more informed decision. The aims of this application are to demonstrate our commitment to the ongoing A2ALL studies, describe established procedures to assure collection of prospective data that is the core mission of the A2ALL consortium, and propose scientific studies that will enhance our understanding of biological responses that are critical for the recovery and long term well being of the donor and recipient. Our concept proposals aim to investigate molecular pathways of regeneration that impact donor and recipient liver function and patterns of alloimmune response in LDLT recipients. 1. Donor Concept Proposal: This proposal will seek to identify molecular patterns of recovery in the donor liver remnant and peripheral blood that are indicative of, and predict, the eventual return of liver function and mass. This will be accomplished by correlating gene expression in the remnant lobe and in sequential peripheral blood mRNA profiles, with longitudinal assessment of donor liver regeneration and quantitative liver function testing. 2. Recipient Concept Proposal: Using a randomized clinical trial design, this proposal will investigate whether LDLT facilitates safe minimization of immunosuppression. In a parallel mechanistic study, we will investigate whether peripheral blood cell mRNA profiles offer a noninvasive means of predicting and diagnosing LDLT allograft rejection. The goals laid out in this proposal can be met within the time frame for the extension of A2ALL and take advantage of the existing clinical database, stored donor and recipient specimens that can be used for molecular analysis, and include in the prospective interventional studies recipients that are already enrolled in A2ALL and are eligible and willing to participate in immunosuppression minimization study. PUBLIC HEALTH RELEVANCE: As outcomes improve and more benefits are recognized, there is increased interest in living donor transplantation. Before significant expansion can occur, it is important to determine the consequences of the living donor procedure with regard to donor well-being and recipient outcomes. Potential interventions to improve liver function and regeneration in the donor, and efforts to prolong graft function and minimize side effects of immunosuppression in the recipient can have great impact on long-term outcomes.