Utility of Biomarkers of Rejection and Kidney Injury in Tailoring Liver Transplant Immunosuppression

项目摘要/摘要 分子生物标记物的出现带来了巨大的希望，无论是从诊断的角度还是从能力的角度 及早预测疾病状态，以便为治疗和改变临床结果提供信息。在过去几年里， 研究表明，生物标志物分析在肝脏免疫抑制的管理中具有作用。 移植受者。从我们的CTOT-14研究数据中，我们已经开发出可以早期发现的关键生物标记物 免疫抑制不足(排斥)和过度(慢性肾脏疾病)的迹象，特别是在使用 标准的钙调神经磷酸酶抑制剂治疗。但随着分子诊断准确性的提高，以及技术的进步， 随着平台的发展，关于它们在肝脏管理中的价值的两个重要问题浮出水面 移植受者。首先，生物标记物能否为患者管理提供信息，并优化个性化能力 免疫抑制疗法？第二，我们能描述免疫激活和肾脏损伤的关键途径吗？ 进一步优化生物标记物的使用，寻找新的治疗靶点？我们认为这些问题 构成了生物标记物研究的下一个前沿，因此我们制定了这项建议，以测试一组 与这些问题直接相关的假设。首先，在一项前瞻性的多中心肝脏临床试验中 接受移植的人，我们将挑战“护理标准”，并测试一系列血液生物标志物 侧写可以识别肝移植后有肾损伤风险的患者，还可以指导切除 肾毒性钙调神经磷酸酶抑制剂治疗安全，不会增加急性排斥反应。要做到这一点 目标：我们将利用在CTOT-14验证研究中开发的免疫和肾脏生物标记物来 检测排斥反应和肾脏损伤的早期迹象以加强钙调神经磷酸酶抑制剂的积极、安全的停药 倾向于使用无肾毒性的mTOR-抑制剂。这种生物标记物引导的介入方法将进行对照测试 目前的标准管理，并将患者风险分层为需要或不需要的患者 干预措施。其次，我们将利用临床试验样本收集来更深入地了解 导致拒绝，或者是什么是保护拒绝。我们将通过执行 在干预期间进行广泛的血液免疫细胞、抗体、基因组和蛋白质组谱分析 最好找出通向我们结果的道路。此外，我们还将同步表演新肾 在我们独特的队列中，成像生物标记物询问是什么导致肾脏损伤与保护。总而言之，临床 试验和伴随的机制研究将使我们能够跨过生物标志物研究的下一个前沿 移植，即使用生物标记物监测免疫反应和药物状态的能力 毒性，为治疗决策提供信息。我们的临床数据和生物库样本将为 并促进可转化为临床实践的新一代分子诊断。

Project Summary/Abstract The advent of molecular biomarkers holds great promise, both from a diagnostic perspective as well as the ability to predict a disease state early enough to inform therapy and change clinical outcomes. In the last several years, studies have suggested a role for biomarker profiling in the management of immunosuppression in liver transplant recipients. From our CTOT-14 study data, we have developed key biomarkers that can detect early signs of under- (rejection) and over- (chronic kidney disease) immunosuppression, particularly with use of standard calcineurin-inhibitor therapy. But as the accuracy of molecular diagnostics improves, and as technology platforms evolve, two important questions have surfaced regarding their value in the management of liver transplant recipients. First, can biomarkers inform patient management and optimize the ability to personalize immunosuppressive therapy? Second, can we characterize key pathways of immune activation and kidney injury to further optimize the use of biomarkers and identify new therapeutic targets? We believe that these questions comprise the next frontier in biomarker research, and we have therefore formulated this proposal to test a set of hypotheses that relate directly to these questions. First, in a prospective multi-center clinical trial of liver transplant recipients, we will challenge the `standard of care' and test the hypothesis that serial blood biomarker profiling can identify patients at risk of kidney injury after liver transplantation and also guide the removal of nephrotoxic calcineurin-inhibitor therapy safely without adversely increasing acute rejection. To achieve this objective, we will leverage these immune and kidney biomarkers developed in our CTOT-14 validation study to detect early signs of rejection and kidney injury to enhance proactive, safe withdrawal of calcineurin-inhibitors in favor of non-nephrotoxic mTOR-inhibitors. This biomarker-guided interventional approach will be tested against current standard management and also risk-stratify patients into those needing or not needing such interventions. Second, we will leverage the clinical trial sample collections to gain deeper understanding of what leads to rejection or alternatively what is protective of rejection. We will accomplish this by performing an extensive battery of blood immune cell, antibody, genomic and proteomic profiling during the interventions to best identify the pathways leading to our outcomes. In addition, we will simultaneously perform novel kidney imaging biomarkers to ask what leads to kidney injury vs. protection in our unique cohorts. Together, the clinical trial and accompanying mechanistic studies will allow us to cross the next frontier in biomarker research in transplantation, namely the ability to use biomarkers to monitor the state of immune responsiveness and drug toxicity to inform therapeutic decisions. Our clinical data and bio-banked samples will create a new resource for the community and facilitate a new generation of molecular diagnostics translatable into clinical practice.