A new humanized mouse model of chronic hepatitis B

一种新的慢性乙型肝炎人源化小鼠模型

• 批准号: 8707714
• 负责人: MICHAEL ROBEK
• 金额: $ 20.68万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-12 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707714
• 关键词: Accounting; Acute; Affect; Age; Animals; Antiviral Agents; Biological Models; Cells; Cellular biology; Chronic; Chronic Hepatitis B; Disease; Engraftment; Genes; Genome; Goals; Hematopoietic; Hepatitis B; Hepatitis B Core Antigen; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatitis B e Antigens; Hepatocyte; Human; Immune; Immune response; Immune system; Immunosuppression; Immunotherapeutic agent; Infection; Inflammation; Injection of therapeutic agent; Knock-in Mouse; Lead; Length; Liver; Liver Cirrhosis; Maintenance; Malignant neoplasm of liver; Methodology; Methods; Modeling; Mouse Strains; Mus; Pathology; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Physiological; Plasmids; Population; Primary carcinoma of the liver cells; Production; RNA; Reproducibility; Research; Research Personnel; Risk; Serum; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Vaccination; Viral Antigens; Viremia; Virus; Virus Replication; chemokine receptor; cytokine; exhaustion; global health; immunopathology; improved; in vivo; liver infection; liver inflammation; liver injury; mouse model; novel; public health relevance; receptor; reconstitution; response; trafficking; transcription factor; viral DNA

PROJECT SUMMARY Chronic hepatitis B virus (HBV) infection is a significant global health problem because it substantially increases the risk for developing liver cirrhosis and hepatocellular carcinoma. Worldwide, more than 240 million people are chronically infected with HBV, and infection with this virus accounts for ~80% of all liver cancer. The human immune system can eliminate HBV from the liver, yet often fails to do so, especially in those who become infected at an early age. HBV persistence is due in part to immunoevasive tactics employed by the virus as well as host-driven immunosuppression of antiviral immune responses during chronic infection that serves to limit inflammation and immunopathology. Thus, therapeutic manipulation of the antiviral T cell response represents a promising method of treatment to cure the infection. However, the lack of suitable model systems in which to evaluate new immunotherapeutic approaches represents a critical barrier in the field. The overall goal of this proposal is to develop a new mouse model for HBV that unites the physiological relevancy of the human immune system with the convenience and reproducibility of genetically defined transgenic mice. Our general approach will be to combine well-characterized mouse models of HBV replication with a new strain of "humanized" mice whose immune systems can be efficiently reconstituted with T cells from HBV-infected patients. We will then test the hypothesis that engraftment of human immune cells in these mice will lead to an HBV-specific immune response in the liver, and that this response will reflect the disease status of the human donor. To evaluate our hypothesis, we will carry out two specific aims. First we will introduce HBV replication into the liver of a mouse strain that contains a number of knock-in gene-humanizations to improve the engraftment, differentiation, and maintenance of human hematopoietic populations in the animals. Second, we will engraft these mice with PBMC from acute-resolved and chronic HBV patients, and characterize how these immune cells traffic to the liver and respond to hepatocytes that produce HBV antigens. The intent of developing this model system is to provide new means for studying the human HBV immune responses in vivo. This will fill a critical unmet need, and we anticipate that this system will have wide application for both basic and translational HBV research to understand T cell functionality in chronic HBV infection, evaluate novel immunotherapeutic approaches, and identify determinants of HBV immunopathogenesis. Such analyses could have a substantial impact on the study and treatment of chronic liver infections in humans.

项目概要 慢性乙型肝炎病毒 (HBV) 感染是一个重大的全球健康问题，因为 增加患肝硬化和肝细胞癌的风险。全球超过 240 数百万人慢性感染乙型肝炎病毒，感染该病毒的人约占所有肝脏的80% 癌症。人体免疫系统可以消除肝脏中的乙型肝炎病毒，但往往无法做到这一点，尤其是在 那些在很小的时候就被感染的人。乙型肝炎病毒的持续存在部分是由于免疫逃避策略 病毒所利用的以及慢性病期间宿主驱动的抗病毒免疫反应的免疫抑制 用于限制炎症和免疫病理学的感染。因此，抗病毒药物的治疗操作 T 细胞反应代表了一种有前途的治疗感染的方法。但由于缺乏合适的 评估新免疫治疗方法的模型系统是免疫治疗中的一个关键障碍 场地。该提案的总体目标是开发一种新的 HBV 小鼠模型，该模型将生理学和 人类免疫系统与遗传定义的便利性和可重复性的相关性 转基因小鼠。我们的一般方法是结合充分表征的乙肝病毒复制小鼠模型 一种新的“人源化”小鼠品系，其免疫系统可以用来自 乙肝病毒感染者。然后我们将测试人类免疫细胞植入这些小鼠体内的假设 会在肝脏中引起乙型肝炎病毒特异性免疫反应，并且这种反应将反映疾病状态 人类捐赠者的。为了评估我们的假设，我们将实现两个具体目标。首先我们来介绍一下 乙型肝炎病毒复制到含有许多敲入基因人源化的小鼠品系的肝脏中 改善人类造血细胞群在动物体内的植入、分化和维持。 其次，我们将来自急性缓解和慢性 HBV 患者的 PBMC 移植到这些小鼠中，并且 描述这些免疫细胞如何运输至肝脏并对产生 HBV 的肝细胞作出反应 抗原。开发该模型系统的目的是为研究人类乙型肝炎病毒提供新的手段 体内的免疫反应。这将填补一个未满足的关键需求，我们预计该系统将具有广泛的应用前景 应用于基础和转化 HBV 研究，以了解慢性 HBV 中的 T 细胞功能 感染、评估新的免疫治疗方法并确定 HBV 的决定因素 免疫发病机制。此类分析可能对慢性病的研究和治疗产生重大影响 人类肝脏感染。