Identifying and modulating therapeutic targets in a model of hepatitis B

乙型肝炎模型中的识别和调节治疗靶点

• 批准号: 9765159
• 负责人: JODY L BARON
• 金额: $ 56.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-16 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765159
• 关键词: 5 year old; Acute Hepatitis; Address; Adult; Age; Animal Model; Antigens; Antiviral Response; B cell differentiation; B-Lymphocytes; Biology; CD8-Positive T-Lymphocytes; CXCL13 gene; Cells; Cessation of life; Child; Chronic; Chronic Hepatitis; Chronic Hepatitis B; Correlative Study; Data; Development; Disease; Disease Outcome; Double Stranded DNA Virus; Evaluation; Event; Excision; Exhibits; Exposure to; Generations; Goals; Government; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Helper-Inducer T-Lymphocyte; Hepatic; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Virus; Human; Immune; Immune System Diseases; Immune response; Immune signaling; Immune system; Immunity; Immunocompetence; Immunoglobulin Class Switching; Individual; Infant; Infection; Laboratories; Lead; Leukocytes; Ligands; Liver; Liver Failure; Liver diseases; Lymphoid; Lymphoid Cell; Lymphoid Tissue; Mediating; Modeling; Motion; Mus; Outcome; Pathway interactions; Persons; Population Group; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Process; Production; Research; Resolution; Role; Signal Transduction; Structure; T-Lymphocyte; T-cell diversity; TNFSF4 gene; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transgenic Mice; Transgenic Model; Viral; Viral Antigens; Virus; Virus Diseases; Work; adaptive immune response; age related; base; cell type; chemokine; chronic infection; cytokine; defined contribution; differentiated B cell; exhaustion; immune activation; immunoregulation; interleukin-22; intrahepatic; liver biopsy; liver development; liver injury; macrophage; monocyte; mouse model; neonatal infection; new therapeutic target; novel; pathogenic virus; programs; recruit; response; seroconversion; therapeutic candidate; therapeutic target; tool; tumor necrosis factor ligand superfamily member 4; young adult

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.

项目概要： 乙型肝炎病毒 (HBV) 是一种小型、部分双链 DNA 病毒，可引起急性和慢性肝炎 肝炎。据估计，全球有 4 亿人患有慢性感染，其中许多人因肝病而过早死亡 失败和原发性肝癌（HCC）。解决 HBV 感染的机会取决于年龄：大约 90% 的新生儿感染转为慢性，而至少 90% 的成人感染可自行清除。这是 人们普遍认为，广泛且多样化的适应性免疫反应对于清除急性乙型肝炎病毒感染非常重要。 然而，为什么一个人会产生或无法产生有利的反应，以及为什么这种能力会因人而异。 年龄，才刚刚开始被理解。 HBV 免疫发病机制的研究受到限制，因为 HBV 仅感染远交物种，其 免疫系统很难检查，而且它不会感染老鼠，而老鼠是大多数研究工具的物种 免疫机制已经发展。我的实验室开发了原发性转基因小鼠模型 HBV 感染模仿人类 HBV 清除和持久性的关键差异，包括与年龄相关的 人类乙型肝炎病毒感染结果的二分法。该模型使我们能够解决 HBV 的基本问题 生物学： 1. 为什么免疫反应和疾病结果会根据个体年龄的不同而不同 感染时间？ 2. 促进病毒控制的免疫机制是什么？这些机制与病毒有何不同？ 导致慢性病毒感染的免疫机制？ 3. 免疫调节途径是否可以确定 有效的乙肝免疫是否重要？是否会导致无效的免疫反应转向病毒控制？ 我们使用该模型的集体数据以及我们对人类的相关研究表明，免疫 乙型肝炎病毒的启动发生在肝脏中，有效的免疫启动需要白细胞的精心形成 由巨噬细胞和单核细胞锚定的簇。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，对于特定 CD8+ T 和 B 细胞的最佳生成至关重要 对于病毒清除至关重要的反应。此外，肝脏 APC 的成熟及其年龄依赖性 趋化因子 CXCL13 的表达对于 B 细胞分化和类别转换至关重要，而年龄依赖性 共刺激配体 OX40L 的表达解释了肝脏中 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新的范式来解释年龄依赖性乙型肝炎 持久性和确定治疗靶点，还有许多与细胞和相关的未解答的问题 参与肝白细胞结构形成和有效免疫启动的途径。我们的 该提案探讨了以下假设：第 3 组先天淋巴细胞 (ILC3) 的常驻肝脏群体是 对于淋巴组织的发育和/或有效乙肝病毒免疫的启动很重要。此外， 我们的目标是肝脏 ILC3 的发育以及 CXCL13 和 OX40L 的表达，以倾斜免疫 年轻和“慢性 HBV 小鼠”对病毒控制和 HBsAb 血清转化的反应。