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

项目总结/摘要 分子生物标志物的出现有很大的希望，无论是从诊断的角度来看，以及能力 以足够早地预测疾病状态，从而为治疗提供信息并改变临床结果。在过去的几年里， 研究表明生物标志物分析在肝脏免疫抑制管理中的作用 移植接受者从我们的CTOT-14研究数据中，我们已经开发出了关键的生物标志物，可以在早期发现 免疫抑制不足（排斥反应）和过度（慢性肾病）的体征，特别是使用 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， 随着平台的发展，关于其在肝脏管理中的价值， 移植接受者首先，生物标志物能否告知患者管理并优化个性化的能力 免疫抑制疗法？第二，我们能否描述免疫激活和肾损伤的关键途径 进一步优化生物标志物的使用并确定新的治疗靶点？我们认为这些问题 包括生物标志物研究的下一个前沿，因此我们制定了这一建议，以测试一套 与这些问题直接相关的假设。首先，在一项前瞻性多中心肝脏临床试验中， 移植受者，我们将挑战“护理标准”，并测试一系列血液生物标志物 分析可以识别肝移植后有肾损伤风险的患者， 肾毒性钙调神经磷酸酶抑制剂治疗安全，而不会增加急性排斥反应。实现这一 我们将利用CTOT-14验证研究中开发的这些免疫和肾脏生物标志物， 检测排斥反应和肾损伤的早期体征，以增强钙调神经磷酸酶抑制剂的主动，安全撤药， 支持非肾毒性mTOR抑制剂。这种生物标志物引导的介入方法将在以下方面进行测试： 目前的标准管理，并将患者风险分层为需要或不需要这些 干预措施。第二，我们将利用临床试验样本收集，更深入地了解 导致排斥或者是排斥的保护。我们将通过执行 在干预期间进行了大量的血液免疫细胞、抗体、基因组和蛋白质组分析， 最好的方法是找出通向我们结果的途径。此外，我们将同时进行新的肾脏 成像生物标志物，以询问在我们独特的队列中是什么导致肾损伤还是保护。在一起，临床 试验和伴随的机制研究将使我们能够跨越生物标志物研究的下一个前沿， 移植，即使用生物标志物监测免疫应答和药物治疗状态的能力。 毒性，以告知治疗决策。我们的临床数据和生物库样本将为 社区和促进新一代的分子诊断转化为临床实践。

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.