人鼠嵌合肝小鼠模型的建立及在HBV致病研究中的应用

病毒性肝炎一直是全球范围内一个沉重的肝病负担,其中以乙型肝炎最为严重。由于HBV仅感染灵长类动物,因此其所致肝病很难在动物模型中被复制。人鼠嵌合肝小鼠模型是指将人源肝细胞移植入免疫缺陷的肝损伤小鼠肝内而形成的嵌合体小鼠。由于小鼠肝内嵌合有人肝细胞,可以在其体内模拟HBV的感染,利于进行进一步的机制研究。目前该模型主要以白蛋白启动子调控尿激酶(Alb-uPA)小鼠模型和延胡索酰乙酰乙酸水解酶(Fah~(-/-))小鼠模型为基础,在人源肝组织和外周血中均可检测到HBV,并已应用于HBV突变、HBV基因功能、抗病毒药物效果以及HBV与免疫系统的相互作用等方面的研究。本文就传统HBV感染动物模型的利弊、人鼠嵌合肝小鼠模型的研究进展和改进方法进行综述。

Establishment and application of human liver chimeric mouse models in HBV-induced pathogenesis

Viral hepatitis, especially hepatitis B, has long been heavy burden of liver disease worldwide. However, due to its host spectrum exclusively being primates, HBV infection is hard to be replicated in animal models. Human liver chimeric mouse models are generated from immunodeficient and liver defected mice transplanted with human hepatocytes. Due to chimerism with human hepatocytes, the mouse models can be infected by HBV and liver disease models can be generated. The mechanism by which HBV causes liver diseases can be elucidated accordingly. The models are constructed mainly on the basis of Alb-uPA mouse model and Fah-/- mouse model. HBV can be detected both in the human chimeric liver tissue and peripheral blood of the models. The models have been applied for the investigation of HBV mutations, HBV gene functions, anti-HBV agent effects, the interactions between HBV and immune system. This article reviews the advantages and disadvantages of those HBV infection models and emphasizes the advances and improvement in human liver chimeric mouse models.