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

背景乙肝病毒是一个主要的健康问题，全世界有近3亿人受到影响。肝脏可能会发生长期感染，特别是在生命早期暴露的情况下，这会增加疤痕组织形成、癌症和肝功能衰竭的风险。目前的治疗方法(如替诺福韦、恩替卡韦)耐受性良好，可提供片剂形式，在抑制病毒复制方面非常有效；然而，病毒的痕迹仍然存在，如果过早停止治疗，可能会发生危及生命的炎症。随着未来几年出现新的治疗方法，开发能准确反映肝脏中病毒负担和免疫人群活动的血液测试变得越来越重要。最终，这将使个体与最适当的治疗相匹配，从而将副作用降至最低。研究目的(S)我们的研究项目将探索乙肝病毒在肝脏中的分布，并确定血液中反映感染负担(以及免疫反应)的标志物。设计和方法使用的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，将识别在我们的研究生物库中存储组织样本的慢性乙肝感染者。利用被称为“原位杂交”和“多重抗体染色”的技术，我们将绘制出病毒活性(遗传物质、蛋白质)在肝脏内的分布以及局部免疫细胞的布局。同时，我们将测量血液中的一组分子，并探索它们在多大程度上反映肝脏内的病毒活动。在研究的第二部分，将在英皇书院医院接触100名病人，并在进行临床复查时进行额外的血液测试。在将免疫细胞从血液中分离出来后，将进行一系列实验来评估它们的功能和复制能力；这些细胞被耗尽和无法执行正常保护功能的程度将与血清中的分子(包括TIM3和Spd-1)相关。潜在的应用和好处该研究项目有可能从根本上改变我们对乙肝病毒在肝脏中复制的理解。从临床的角度来看，密切反映病毒活动的血液测试将帮助临床医生决定哪些患者应该开始治疗、治疗的持续时间以及是否适合停药。此外，它们可能有助于识别罹患肝癌的风险最高的人，对这些人应该采取更严格的监测计划。沟通计划我们预计，我们的结果将对未来慢性乙肝患者的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公布，并在医学期刊上发表。此外，我们认识到向病人汇报研究进展的重要性，并会透过在英皇书院医院定期举办的教育计划，以及通讯、网站和本地网络，达致这个目标。

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.