Novel hepatitis B virus infection mouse model using herpes simplex virus type 1 thymidine kinase transgenic mice
Novel hepatitis B virus infection mouse model using herpes simplex virus type 1 thymidine kinase transgenic mice
复制标题
DOI：
10.1111/jgh.15142
复制
发表时间：
2020-07-07
影响因子：
4.1
通讯作者：
Ito，Hiroyasu
中科院分区：
文献类型：
--
作者：
Kanbe，Ayumu;Ishikawa，Tetsuya;Ito，Hiroyasu
背景与目的B型肝炎病毒（HBV）感染的慢性化是HBV特异性免疫应答受损而不能有效清除或治愈感染肝细胞的结果。先前的研究使用了免疫缺陷小鼠，例如单纯疱疹病毒1型胸苷激酶NOD/Scid/IL 2 Rrnull（HSV-TK-NOG）小鼠。然而，在以前的模型中，很难分析免疫反应。在本研究中，我们建立了一种新的HBV感染模型，使用单纯疱疹病毒1型胸苷激酶（HSV-TK）的小鼠，其中宿主免疫系统是不imported.MethodsHerpessimplexvirustype1胸苷激酶小鼠腹腔注射更昔洛韦（GCV）。GCV注射后7天，GCV处理的小鼠移植1 × 106肝细胞从HBV-转基因（HBV-Tg）mice. ResultsHSV-TK小鼠血清丙氨酸氨基转移酶水平增加1和2周后GCV注射。使用含有释放酶的消化培养基，HBV‐Tg小鼠全肝肝细胞的数量和活力显著增加。在HBsAg阳性肝细胞移植后至少20周观察肝组织中的B型肝炎表面抗原（HBsAg）阳性区域。此外，我们还检测了移植后血清中的HBsAg。移植后4周，HBV-Tg肝细胞替代小鼠的HBsAg水平升高。此外，我们检查了HSV-TK小鼠的免疫应答。替换小鼠中B型肝炎表面抗体水平的增加维持了20周。此外，干扰素-γ-产生细胞增加non-replaced mice.ConclusionsA新的HBV感染小鼠模型将有助于了解HBV耐受机制类似于人类慢性HBV感染患者，并可用于开发一种新的策略来治疗慢性HBV感染。
Background and AimThe chronicity of hepatitis B virus (HBV) infection is the result of impaired HBV‐specific immune responses that cannot eliminate or cure the infected hepatocytes efficiently. Previous studies have used immunodeficient mice such as herpes simplex virus type 1 thymidine kinase NOD/Scid/IL2Rrnull(HSV‐TK‐NOG) mice. However, it is difficult to analyze the immune response in the previous models. In the present study, we established a novel HBV infection model using herpes simplex virus type 1 thymidine kinase (HSV‐TK) mice in which the host immune system was not impaired.MethodsHerpes simplex virus type 1 thymidine kinase mice were injected intraperitoneally with ganciclovir (GCV). Seven days after GCV injection, GCV‐treated mice were transplanted with 1 × 106hepatocytes from HBV‐transgenic (HBV‐Tg) mice.ResultsSerum alanine aminotransferase levels in HSV‐TK mice increased 1 and 2 weeks after GCV injection. The number and viability of hepatocytes from the whole liver of HBV‐Tg mice significantly increased using digestion medium containing liberase. Hepatitis B surface antigen (HBsAg)‐positive areas in the liver tissue were observed for at least 20 weeks after HBsAg‐positive hepatocyte transplantation. In addition, we measured HBsAg in the serum after transplantation. HBsAg levels in HBV‐Tg hepatocyte‐replaced mice increased 4 weeks after transplantation. Furthermore, we examined the immune response in HSV‐TK mice. The increase in hepatitis B surface antibody levels in replaced mice was maintained for 20 weeks. Also, interferon‐γ‐producing cells were increased in non‐replaced mice.ConclusionsA novel HBV infection mouse model will help to understand the mechanisms of HBV tolerance similar to human chronic HBV‐infected patients and can be used to develop a new strategy to treat chronic HBV infection.