A new humanized mouse model of chronic hepatitis B

项目总结 慢性乙肝病毒感染是一个重大的全球健康问题，因为它在很大程度上 增加发展为肝硬变和肝细胞癌的风险。在全球，超过240个 数百万人慢性感染乙肝病毒，感染这种病毒的人约占所有肝脏的80% 癌症。人类免疫系统可以清除肝脏中的乙肝病毒，但往往无法做到这一点，特别是在 那些在很小的时候就被感染的人。乙肝病毒的持久性在一定程度上是由于免疫逃避策略 由病毒和宿主驱动的免疫抑制抗病毒免疫反应在慢性 用于限制炎症和免疫病理的感染。因此，抗病毒药物的治疗性操作 T细胞反应是治愈感染的一种很有前途的治疗方法。然而，缺乏合适的 评估新的免疫治疗方法的模型系统是在 菲尔德。这项提议的总体目标是开发一种新的乙肝病毒小鼠模型，将生理上的 人类免疫系统与基因定义的方便性和重复性的相关性 转基因小鼠。我们的总体方法将是结合具有良好特征的乙肝病毒复制的小鼠模型 一种新的“人源化”小鼠，其免疫系统可以有效地与来自 乙肝病毒感染者。然后，我们将检验这样一种假设，即人类免疫细胞在这些小鼠体内植入 将导致肝脏中的乙肝病毒特异性免疫反应，这种反应将反映疾病状态 人类捐赠者的身份。为了评估我们的假设，我们将实现两个具体目标。首先，我们将介绍 将乙肝病毒复制到含有多个敲入基因人源化的小鼠的肝脏中 改善人的造血细胞在动物体内的植入、分化和维持。 其次，我们将把急性缓解和慢性乙肝患者的PBMC移植到这些小鼠身上，并 描述这些免疫细胞如何进入肝脏并对产生乙肝病毒的肝细胞作出反应 抗原。开发这一模型系统的目的是为研究人类乙肝病毒提供新的手段 体内的免疫反应。这将填补一个关键的未得到满足的需求，我们预计这一系统将有广泛的 应用基础研究和翻译研究了解慢性乙肝患者的T细胞功能 感染，评估新的免疫治疗方法，并确定乙肝病毒的决定因素 免疫致病机制。这种分析可能会对慢性阻塞性肺疾病的研究和治疗产生重大影响。 人类的肝脏感染。

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.