Defining the relationship between peripheral markers, intrahepatic HBV activity and the host immune response.

定义外周标志物、肝内 HBV 活性和宿主免疫反应之间的关系。

• 批准号: MR/Y001168/1
• 负责人: James Lok
• 金额: $ 38.1万
• 依托单位: King's College Hospital
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY001168%2F1
• 关键词: Defining; relationship; between; peripheral; markers

BackgroundHepatitis B virus (HBV) is a major health problem with almost 300 million people affected worldwide. Long-term infection may be established in the liver, especially if exposure occurs early in life, and this increases the risk of scar tissue formation, cancer and liver failure. Current treatments (such as tenofovir, entecavir) are well tolerated, available in tablet form and highly effective at suppressing viral replication; however, traces of the virus persist and life-threatening inflammation may occur if treatment is stopped prematurely. As new treatments become available over the next few years, it is increasingly important to develop blood tests that closely reflect the burden of virus in the liver and activity of the immune population. Ultimately, this will allow individuals to be matched with the most appropriate treatments and thus minimise side effects. Aim(s) of the researchOur research project will explore the distribution of hepatitis B virus in the liver and identify markers in the bloodstream that reflect the burden of infection (as well as the immune response).Design and methods usedThe research will be conducted across three sites, namely King's College Hospital (London), Francis Crick Institute (London) and the Nuffield Department of Medicine (Oxford). In the first part of the project, individuals with chronic hepatitis B infection who have tissue samples stored in our research biobank, will be identified. Using techniques called "in-situ hybridisation" and "multiplex antibody staining", we will map the distribution of viral activity (genetic material, proteins) within the liver and the layout of local immune cells. In parallel, we will measure a panel of molecules in the bloodstream and explore how closely they reflect viral activity within the liver. In the second part of the study, a cohort of patients (n=100) will be approached at King's College Hospital and extra blood tests will be taken at the time of clinical review. After isolating immune cells from the bloodstream, a series of experiments will be conducted to assess their function and ability to replicate; the extent to which these cells are "exhausted" and unable to carry out their normal protective functions will be correlated with molecules in the serum (including Tim3 and sPD-1).Potential applications and benefitsThe research project has the potential to fundamentally change our understanding of HBV replication in the liver. From a clinical perspective, blood tests that closely reflect viral activity will help clinicians to decide which patients should be started on treatment, the duration of therapy, and suitability for withdrawal. In addition, they may help to identify those at greatest risk of developing liver cancer, in whom a more stringent surveillance programme should be adopted. Communication planWe envisage that our results will have a significant impact on the way patients with chronic hepatitis B infection are managed in the future, and we want to maximise visibility amongst other experts in the field. To achieve this, the data will be presented at international conferences and published in medical journals. In addition, we recognise the importance of updating patients on the progress of the research, and this will be achieved through educational programmes that we run regularly at King's College Hospital, as well as newsletters, websites and local networks.

背景B型肝炎病毒（HBV）是一种严重的健康问题，全世界有近3亿人感染HBV。长期感染可能会在肝脏中建立，特别是如果在生命早期暴露，这会增加疤痕组织形成，癌症和肝功能衰竭的风险。目前的治疗（如替诺福韦，恩替卡韦）耐受性良好，以片剂形式提供，并且在抑制病毒复制方面非常有效;然而，如果过早停止治疗，则病毒的痕迹会持续存在，并且可能发生危及生命的炎症。随着新的治疗方法在未来几年内变得可用，开发密切反映肝脏中病毒负担和免疫群体活动的血液检测变得越来越重要。最终，这将使个人与最合适的治疗方法相匹配，从而最大限度地减少副作用。研究目的我们的研究项目将探索B型肝炎病毒在肝脏中的分布，并确定血流中反映感染负担（以及免疫反应）的标志物。设计和方法研究将在三个地点进行，即国王学院医院（伦敦），弗朗西斯克里克研究所（伦敦）和纳菲尔德医学系（牛津）。在该项目的第一部分，将确定在我们的研究生物库中储存有组织样本的慢性B型肝炎感染者。使用称为“原位杂交”和“多重抗体染色”的技术，我们将绘制肝脏内病毒活性（遗传物质，蛋白质）的分布和局部免疫细胞的布局。与此同时，我们将测量血液中的一组分子，并探索它们与肝脏内病毒活动的密切程度。在研究的第二部分，将在国王学院医院接触一组患者（n=100），并在临床审查时进行额外的血液检查。从血流中分离免疫细胞后，将进行一系列实验，以评估其功能和复制能力;这些细胞“耗尽”且无法发挥正常保护功能的程度将与血清中的分子相关（包括Tim 3和sPD-1）潜在的应用和益处该研究项目有可能从根本上改变我们对肝脏中HBV复制的理解。从临床角度来看，密切反映病毒活性的血液检测将有助于临床医生决定哪些患者应该开始治疗，治疗持续时间以及是否适合停药。此外，它们可能有助于确定那些发展肝癌的风险最大的人，应该采取更严格的监测计划。我们设想我们的研究结果将对慢性B型肝炎感染患者的未来管理方式产生重大影响，我们希望在该领域的其他专家中最大限度地提高知名度。为了实现这一目标，这些数据将在国际会议上展示，并发表在医学期刊上。此外，我们认识到向患者更新研究进展的重要性，这将通过我们在国王学院医院定期开展的教育计划以及时事通讯，网站和当地网络来实现。