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.

背景肝炎病毒（HBV）是一个主要的健康问题，全世界有近3亿人受到影响。可以在肝脏中建立长期感染，尤其是在暴露于生命早期的情况下，这增加了疤痕组织形成，癌症和肝衰竭的风险。当前的治疗方法（例如Tenofovir，Entecavir）的耐受性良好，以片剂形式获得，并且可以抑制病毒复制；但是，如果过早停止治疗，可能会持续存在病毒的痕迹，并可能发生威胁生命的炎症。随着未来几年新疗法的可用性，开发血液检查越来越重要。最终，这将使个人与最合适的治疗相匹配，从而最大程度地减少副作用。研究人员研究项目的目的将探索肝炎病毒在肝脏中的分布，并确定反映感染负担的血液中的标记（以及免疫反应）。设计和使用的方法将在三个地点进行研究，即国王学院（伦敦），弗朗西斯·克里克学院（Francis Crick Instute）（弗朗西斯·克里克学院（Francis Crick）学院（伦敦）和Nuffield iffield Sercarion（Nuffieldield Sercyne）。在该项目的第一部分中，将确定患有慢性乙型肝炎感染的患者在我们的研究生物库中存储的组织样本。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（遗传材料，蛋白质）的分布和局部免疫细胞的布局。同时，我们将在血液中测量一组分子，并探索它们在肝脏内反映病毒活性的程度。在研究的第二部分中，国王学院医院将接触一系列患者（n = 100），并在临床检查时进行额外的血液检查。从血液中分离出免疫细胞后，将进行一系列实验以评估其复制功能和能力。这些细胞“耗尽”并且无法执行其正常保护功能的程度将与血清中的分子相关（包括TIM3和SPD-1）。潜在的应用和受益，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。从临床的角度来看，紧密反映病毒活性的血液检查将帮助临床医生确定应在治疗，治疗持续时间以及适合戒断的患者中开始哪些患者。此外，它们可能有助于确定患有肝癌的风险最大的人，其中应采用更严格的监测计划。 Communication Planwe设想，我们的结果将对未来慢性乙型肝炎感染的患者进行严重影响，我们希望最大程度地提高该领域其他专家的知名度。为了实现这一目标，数据将在国际会议上介绍并在医学期刊上发布。此外，我们认识到更新患者有关研究进展的重要性，这将通过我们在国王学院医院定期运行的教育计划以及新闻通讯，网站和本地网络来实现。