高复制HBV转基因小鼠模型对抗乙型肝炎病毒药物的效应研究

 目的：研究高复制HBV转基因小鼠模型对抗乙肝病毒药物的效应评价。 方法： 选用抗乙肝药物拉咪呋啶、大剂量重组乙肝蛋白疫苗、α-1b型干扰素和RNA干扰在转基因小鼠进行药效及作用机制评价。 结果：拉咪呋啶、重组乙肝疫苗、α-1b型干扰素均可使HBV转基因小鼠血清中HBV DNA滴度显著降低。其中后两者还可提高机体脾细胞IL-2和IFN-γ的水平及使分泌IFN-γ脾细胞Elispot斑点数明显增加。将RNA干扰表达载体pU6-siHBV质粒尾静脉注入小鼠体内。注射后5 d血清HBsAg下降56.7%,抑制作用持续14 d。肝脏免疫组化显示HBcAg阳性细胞明显减少，但血清HBV DNA定量无明显降低。 结论： 本近交系高复制HBV转基因小鼠模型对抗乙肝药物药效学评估是可靠、可行的。

Use of high-level HBV replication transgenic mice for evaluating drugs treating hepatitis B virus

AIM: To study the high-level HBV replication transgenic mice for evaluation of drugs treating hepatitis B virus. METHODS: The HBV transgenic mice were treated respectively with lamivudine, large dose recombinant hepatitis B protein vaccine, α-1b interferon, siRNA to evaluate their pharmacodynamics and mechanism of action. RESULTS: HBV DNA titre was reduced significantly in transgenic mice which were treated with lamivudine (100 mg·kg_^-1·d^-1), recombinant hepatitis B protein vaccine (HBsAg 6 μg/mouse), α-1b interferon (50 μg /mouse), respectively. Recombinant hepatitis B protein vaccine and α-1b interferon promoted the level of IL-2 and IFN-γ and increased the Elispot number of spleen cells secreting IFN-γ in the treated transgenic mice. HBV transgenic mice were treated with RNAi expression vector pU6-siHBV against HBV through vena caudalis by hydrodynamics technique. Five days later, the level of serum HBsAg was reduced by 56.7% and the inhibition lasted at least 14 days.The HbcAg (+) cells were decreased obviously by immunohistochemistry detection in liver tissue, but the RNAi did not reduce the serum HBV DNA titre. CONCLUSION: These inbreeding high-level HBV replication transgenic mice are reliable and feasible for evaluating the anti-HBV drugs and have its economical and convenient superiority.