Identifying and modulating therapeutic targets in a model of hepatitis B

描述（由申请人提供）：B肝炎病毒（HBV）是一种小的，部分双链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，许多人因肝功能衰竭和原发性肝癌（HCC）而过早死亡。清除HBV感染的机会取决于年龄：大约90%的新生儿感染成为慢性，而至少90%的成人感染是自发清除的。普遍认为广泛多样的适应性免疫应答在清除急性HBV感染中是重要的。然而，为什么一个人会产生或不能产生一个有利的反应，以及为什么这种能力会随着年龄的变化而变化，这是未知的。 HBV免疫发病机制的研究受到限制，因为病毒只感染免疫系统难以检查的远系繁殖物种，而不感染小鼠，大多数研究免疫学的工具都是在小鼠中开发的。为了解决这个问题，我们开发了第一个实验系统来解决年轻人和成年人非常早期HBV感染中免疫应答的机制差异。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设。在这些数据之前，目前的范式假定“免疫系统不成熟”和“新生儿对HBV的耐受性”是6-8岁年轻人中病毒持久性大大增加的基础，但这尚未得到机械解释或明确验证。我们的数据表明，肝脏巨噬细胞和单核细胞的不成熟显着有助于在新生儿和幼儿的肝脏中的效应细胞的免疫启动环境的不成熟，从而显着地有助于他们无法产生有效的免疫应答HBV。我们的建议旨在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，使用本提案中概述的模型检查了促进HBV持续存在的改变的免疫引发的可逆性。最后，基础设施是在适当的位置，以测试的概念utilityof这个模型系统，通过确认的结果，使用人类肝脏活检。

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.