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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

基本信息

批准号：
10218014
负责人：
JODY L BARON
金额：
$ 54.83万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-16 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218014
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

项目摘要

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.

项目总结: