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: 9977122
• 负责人: JODY L BARON
• 金额: $ 57.2万
• 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/9977122
• 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; Immunomodulators; 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; 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： B型肝炎病毒（HBV）是一种小的、部分双链的DNA病毒， 肝炎全世界估计有4亿人慢性感染，许多人因肝脏而过早死亡。 失败和原发性肝癌（HCC）。解决HBV感染的机会取决于年龄：约90% 的新生儿感染变成慢性的，而至少90%的成人感染是自发清除的。是 广泛而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，为什么一个人产生，或未能产生，一个有利的反应，为什么这种能力随着 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仅感染远交种， 免疫系统很难检查，而且它不会感染小鼠，而小鼠是大多数研究工具的物种。 免疫机制已经发展。我的实验室已经开发出转基因小鼠模型， HBV感染模拟HBV清除和人类持续性的关键差异，包括年龄相关的 人类HBV感染结局的二分法。这种模式使我们能够解决HBV中的基本问题 生物学：1.为什么免疫反应和疾病的结果不同，取决于个人的年龄在 感染的时间？2.促进病毒控制的免疫机制是什么？ 导致慢性病毒感染的免疫机制3.免疫调节途径是否可以被识别， 在有效的HBV免疫中是否重要，使无效的免疫应答向病毒控制倾斜？ 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 对HBV的启动发生在肝脏，有效的免疫启动需要协调白细胞的形成， 由巨噬细胞和单核细胞锚定的簇。有效的HBV免疫需要肝TFH细胞 启动和IL-21在肝脏中的产生，其中它对于特异性CD 8 + T和B细胞的最佳产生是必需的 对于病毒清除至关重要的反应。此外，肝APC的成熟及其年龄依赖性 趋化因子CXCL 13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OX 40 L的表达解释了肝脏中TFH引发和IL-21产生的差异。 虽然这些新的数据开始帮助我们制定一个新的范式来解释年龄依赖性HBV 持久性和确定治疗靶点，有许多未回答的问题有关的细胞和 参与肝白细胞结构形成和有效免疫启动的途径。我们 该提案探讨了以下假设，即第3组先天淋巴样细胞（ILC 3）的常驻肝脏群体是 对于淋巴组织的发育和/或有效HBV免疫的启动是重要的。此外，本发明还提供了一种方法， 我们的目标是靶向肝ILC 3的发展，以及CXCL 13和OX 40 L的表达，以使免疫系统发生倾斜。 在年轻和“慢性HBV小鼠”中对病毒控制和抗HBV抗体血清转换的应答。