Identifying and modulating therapeutic targets in a model of hepatitis B

描述(申请人提供)：乙肝病毒(乙肝病毒)是一种小的、部分双链的DNA病毒，可引起急性和慢性肝炎。据估计，全世界有4亿人慢性感染，其中许多人因肝功能衰竭和原发性肝癌(HCC)而过早死亡。清除乙肝病毒感染的机会取决于年龄：大约90%的新生儿感染成为慢性感染，而至少90%的成人感染是自发清除的。人们普遍认为，广泛和多样化的适应性免疫反应对于清除急性乙肝病毒感染是重要的。然而，为什么一个人会产生或不会产生有利的反应--以及为什么这种能力会随着年龄的变化而变化--是未知的。由于病毒只感染免疫系统难以检测的杂交物种，而不感染小鼠，因此对乙肝免疫致病机理的研究一直很有限。大多数免疫学研究工具都是在小鼠身上开发出来的。为了解决这一问题，我们开发了第一个实验系统，以解决年轻人和成年人在非常早期的乙肝病毒感染中免疫反应的机制差异。这个实验系统产生的数据导致了基于实验而不是推测的新假说。在这些数据之前，目前的研究范式假设，“免疫系统不成熟”和“新生儿对乙肝病毒的耐受性”是6-8岁儿童病毒持久性大大增加的基础，但这还没有得到机械解释或明确验证。我们的数据表明，肝巨噬细胞和单核细胞的不成熟是新生儿和幼儿肝脏效应细胞免疫启动环境不成熟的重要原因，从而导致他们无法产生对乙肝病毒的有效免疫应答。我们的建议试图开始机械地理解不成熟的细胞和信号，以及受这种不成熟影响的细胞和信号。此外，本提案中概述的模型的使用检查了改变的免疫启动的可逆性，该改变促进了乙肝病毒的持久性。最后，基础设施已经到位，通过使用人类肝脏活组织检查确认研究结果，来测试该模型系统的概念性效用。

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a small, partially double-stranded DNA virus that causes acute and chronic hepatitis. An estimated 400 million people are chronically infected worldwide, many suffering early death due to liver failure and primary liver cancer (HCC). The chance of clearing HBV infection is age dependent: approximately 90% of neonatal infections become chronic, whereas at least 90% of adult infections are cleared spontaneously. It is generally accepted that a broad and diverse adaptive immune response is important in clearing acute HBV infection. However, why an individual generates, or fails to generate, a favorable response-and why this capability varies with age-is unknown. The study of HBV immunopathogenesis has been limited because the virus only infects outbred species whose immune systems are difficult to examine, and does not infect mice, the species in which most of the tools to study immunology have been developed. To address this, we have developed the first experimental system to address mechanistic differences in immune responses in very early HBV infection in young and adult humans. This experimental system has produced data that has led to new hypotheses based on experimentation rather than speculation. Prior to these data, the current paradigm posits that "immune system immaturity", and "neonatal tolerance" to HBV underpins the greatly increased viral persistence in the young 6-8, but this has not been mechanistically explained or definitively validated. Our data suggest that immaturity of liver macrophages and monocytes significantly contributes to the immaturity of the immune priming environment of effector cells in the livers of newborns and young children and thus contributes significantly to their inability to generate an effective immune response to HBV. Our proposal seeks to begin to mechanistically understand the cells and signals that are immature, and the cells and signals that are affected by this immaturity. Furthermore, the use of the model outlined in this proposal examines the reversibility of the altered immune priming that facilitates HBV persistence. Finally, the infrastructure is in place to test the conceptual utilityof this model system by confirmation of findings using human liver biopsies.