Overcoming HBV immune tolerance to eliminate HBsAg positive hepatocytes via pre administration of GM CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice
Granulocyte macrophage colony stimulating factor (GM CSF) is known to be a potential vaccine adjuvant despite contradictory results from animal and human studies. The discrepancies may be due to the different doses and regimens of GM CSF that were used, given that either mature or immature dendritic cells (DCs) could be induced under different conditions. To test the hypothesis that GM CSF can be used as a novel adjuvant for a hepatitis B virus (HBV) therapeutic vaccine, we administered GM CSF once per day for three days prior to vaccination with recombinant HBV vaccine (rHBVvac) in mice. We observed greater DC maturation in these pre treated animals at day 3 as compared to day 1 or day 2 of daily GM CSF administration. This strategy was further investigated for its ability to break the immune tolerance established in hepatitis B surface antigen transgenic (HBsAg Tg) animals. We found that the levels of induced anti HBsAg antibodies were significantly higher in animals following three days of GM CSF pre treatment before rHBV vaccination after the third immunization. In addition to the increase in anti HBsAg antibody levels, cell mediated anti HBsAg responses, including delayed type hypersensitivity, T cell proliferation, interferon g production, and cytotoxic T lymphocytes, were dramatically enhanced in the three day GM CSF pre treated group. After adoptive transfers of CD8+ T cells from immunized animals, antigen specific CD8+ T cells were observed in the livers of recipient HBsAg Tg animals. Moreover, the three day pre treatments with GM CSF prior to rHBVvac vaccination could significantly eliminate HBsAg positive hepatocytes, suggesting beneficial therapeutic effects. Therefore, this protocol utilizing GM CSF as an adjuvant in combination with the rHBVvac vaccine has the potential to become a novel immunotherapy for chronic hepatitis B patients.
Cellular and Molecular Immunology