Identifying and modulating therapeutic targets in a model of hepatitis B

项目总结： 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，其中许多人因肝脏而过早死亡。 失败和原发性肝癌(肝癌)。解决乙肝病毒感染的机会取决于年龄：大约90% 大多数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。它是 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能产生有利的反应，以及为什么这种能力因 年龄，才刚刚开始被理解。 对乙肝免疫致病机制的研究一直是有限的，因为乙肝病毒只感染其杂交物种 免疫系统很难检查，而且它不会感染老鼠，而大多数研究工具都是在老鼠身上进行研究的。 免疫机制已经被开发出来。我的实验室已经开发出转基因小鼠模型 在人类体内模拟乙肝病毒清除和持久性的关键差异的乙肝病毒感染，包括与年龄相关的 人类乙肝病毒感染结局的二分法。这个模型使我们能够解决乙肝病毒的基本问题。 生物学：1.为什么免疫反应和疾病结果会因年龄不同而不同 感染时间？2.促进病毒控制的免疫机制是什么？这些机制与 导致慢性病毒感染的免疫机制是什么？3.免疫调节途径能否被识别为 在有效的乙肝免疫中重要的是使无效的免疫反应向病毒控制倾斜？ 我们使用这个模型的集体数据和我们在人类中的相关研究表明，免疫力 乙肝病毒的启动发生在肝脏，而有效的免疫启动需要有秩序地形成白细胞 由巨噬细胞和单核细胞锚定的簇状细胞。有效的乙肝免疫需要肝TFH细胞 肝脏中的启动和IL-21的产生，这是产生特定的CD8+T和B细胞所必需的 对病毒清除至关重要的反应。此外，肝脏APC的成熟及其与年龄的关系 趋化因子CXCL13的表达对B细胞分化和分类转换至关重要，但与年龄有关 共刺激配体OX40L的表达解释了肝脏TFH启动和IL-21产生的差异。 虽然这些新数据开始帮助我们制定一种新的范式来解释年龄依赖的乙肝病毒 为了坚持和确定治疗靶点，有许多与细胞和 参与肝脏白细胞结构的形成和有效免疫的启动的途径。我们的 该方案探索了一种假设，即第三组固有淋巴样细胞(ILC3s)的常驻肝脏种群是 对于淋巴组织的发展和/或有效的乙肝免疫的启动非常重要。此外, 我们的目标是针对肝脏ILC3s的发育，以及CXCL13和OX40L的表达，来倾斜免疫 年轻和“慢性乙肝小鼠”对病毒控制和乙肝表面抗体血清转换的反应。

PROJECT SUMMARY: 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 resolving 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 just beginning to be understood. The study of HBV immunopathogenesis has been limited because HBV only infects outbred species whose immune systems are difficult to examine and it does not infect mice, the species in which most of the tools to study immune mechanisms have been developed. My laboratory has developed transgenic mouse models of primary HBV infection that mimic key differences in HBV clearance and persistence in humans, including the age-related dichotomy in human HBV infection outcome. This model has allowed us to address fundamental questions in HBV biology: 1. Why is the immune response and disease outcome different depending on the age of the individual at the time of infection? 2. What are the immune mechanisms that facilitate viral control, and how do these differ from the immune mechanisms that lead to chronic viral infection? 3. Can immune modulation of pathways identified to be important in effective HBV immunity tilt ineffective immune responses toward viral control? Our collective data using this model and our correlative studies in humans, demonstrate that immune priming to HBV occurs in the liver, and that effective immune priming requires orchestrated formation of leukocyte clusters that are anchored by macrophages and monocytes. Effective HBV immunity requires hepatic TFH cell priming and IL-21 production in the liver, where it is essential for optimal generation of specific CD8+ T and B cell responses that are crucial for viral clearance. Furthermore, maturation of liver APCs and their age-dependent expression of the chemokine CXCL13 is crucial for B cell differentiation and class-switching, while age-dependent expression of the co-stimulatory ligand OX40L explains differences in TFH priming and IL-21 production in the liver. While these new data begin to help us formulate a new paradigm to explain age-dependent HBV persistence and to identify therapeutic targets, there are many unanswered questions related to the cells and pathways involved in the formation of hepatic leukocyte structures and the priming of effective immunity. Our proposal explores the hypothesis that a resident hepatic population of group 3 innate lymphoid cells (ILC3s) is important for the development of lymphoid organization and/or the priming of effective HBV immunity. In addition, we aim to target the development of hepatic ILC3s, and the expression of CXCL13 and OX40L, to tilt the immune response in young and “chronic HBV mice” toward viral control and HBsAb seroconversion.