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

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

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5d血清HBsAg下降56.7%,抑制作用持续14d。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。

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 pharmacedynamics 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 p,g/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 tnmsgenic mice are reliable and feasible for evaluating the anti - HBV drugs and have its economical and convenient superiority.