Identifying and modulating therapeutic targets in a model of hepatitis B

描述（由申请人提供）：乙型肝炎病毒（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4亿人受到慢性感染，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%的新生儿感染变成慢性感染，而至少90%的成人感染是自发清除的。人们普遍认为，广泛而多样的适应性免疫反应在清除急性HBV感染中很重要。然而，为什么一个人产生或未能产生有利的反应，以及为什么这种能力随年龄而变化，这是未知的。HBV免疫发病机制的研究一直受到限制，因为病毒只感染免疫系统难以检测的远交种，而不感染小鼠，而大多数研究免疫学的工具都是在小鼠身上开发的。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早期HBV感染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猜测的新假设。在这些数据之前，目前的范式假设“免疫系统不成熟”和“新生儿对HBV的耐受性”是6-8岁儿童中病毒持久性大大增加的基础，但这尚未得到机制解释或明确证实。我们的数据表明，肝脏巨噬细胞和单核细胞的不成熟严重影响了新生儿和幼儿肝脏中效应细胞的免疫启动环境的不成熟，从而严重影响了它们无法产生有效的HBV免疫应答。我们的建议旨在开始从机械上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，本建议中概述的模型的使用检查了促进HBV持久性的改变免疫启动的可逆性。最后，基础设施已经到位，可以通过确认人类肝脏活检的结果来测试该模型系统的概念效用。

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. PUBLIC HEALTH RELEVANCE: 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 world- wide, 125 million are people chronically infected in the United States, many suffering early death due to liver failure and primary liver cancer (HCC). There are at least one million deaths annually from HBV-related disease. This makes HBV one of the world's most common and serious human pathogens. The immune response to HBV antigens can result in viral clearance by some individuals, or lead to chronic infection and liver disease in others. The age of the individual at the time of infection dictates the likelihood of HBV clearance. Using a new mouse model of human HBV viral clearance and persistence recently developed in my laboratory, we have recently published a manuscript that demonstrates that interleukin-21 is pivotal in determining age-dependent immune responses. Data in this manuscript also provides evidence that IL-21 may be part of an effective primary hepatic immune response to HBV in patients acutely infected with HBV who clear the virus. Also using this model, we have now uncovered a potential role for liver macrophages and the co-stimulatory molecule OX40 and its ligand OX40L, in age-dependent immune response to HBV and disease outcome. Because these cells, their receptors, and their respective ligands can be manipulated, they are appealing therapeutic targets for this important global pathogen. Our proposed research will shed light on HBV disease pathogenesis and will help identify new potential therapeutic targets to prevent the devastating consequences of chronic HBV infection.