Mouse model with age-dependent immune response and immune-tolerance for HBV infection

分类： 生物学 >> 生物医药 分类： 生物学 >> 病毒学 提交时间： 2017-07-11

Xuerui,Yi

摘要： Objective: Viral clearance of human HBV infection largely depends on the age of exposure, so a mouse model with age-dependent immune response and immune-tolerance for HBV infection is essential. Methods: HBVRag1 mice were generated by crossing Rag1-/- mice with HBV-Tg mice. The differences between adult and young HBVRag1 mice were detected after adoptive transfer of splenocytes. Immune tolerance was evaluated by quantitative hepatitis B core antibody (qAnti-HBc) assay, adoptive transfer, and modulation of gut microbiota with antibiotic. Results: After HBVRag1 mouse reconstitution, adult mice showed obvious HBV-dependent inflammation and hepatocytes damage, cleared HBsAg and generated HBsAb and HBcAb, but young mice never developed ALT elevation, and only generated HBcAb with persistence of HBsAg. In addition, for adult mice, more hepatic CD8+T and B cells promoted clearance of HBsAg 30 days after lymphocytes transfer, and for young mice, higher levels of cytokines link to the persistence of viral antigens during initiation of immune response towards HBV. The level of qAnti-HBc increased significantly with the time of adoptive transfer in young mice, but decreased significantly in adult within our model. This mimics kinetic changes of human HBV infection regarding qAnti-HBc level. Also, the age-related tolerance in this model was different from which was in HBV-Tg mice, and can be regulated through modulation of gut microbiota. Meanwhile, GS-9620 can achieve inhibition of HBsAg, but HBV vaccine just clears limited HBsAg within the model. Conclusions: Here, we described a mouse model with age-dependent immune response and immune tolerance of HBV infection which could mimic chronic HBV infection in human. It will open a door for evaluating new therapeutic approaches before clinical trials.

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