title: 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.
abstract: 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-γ 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.
authors.affiliation: Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xianzheng
authors.initials: X
authors.lastname: Wang
authors.affiliation: NCPC New Drug R&D Co., Ltd., Shijiazhuang, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Dong
authors.affiliation: Medical Center of Diagnostics and Treatment for Cervical Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: NCPC New Drug R&D Co., Ltd., Shijiazhuang, China.
authors.forename: Xingjun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Haili
authors.initials: H
authors.lastname: Mi
authors.affiliation: State Key Laboratory for Agro-Biotechnology, College of Biological Science, China Agricultural University, Beijing, China.
authors.forename: Hanqian
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Infectious Disease, Huashang Hospital, Fudan University, Shanghai, China.
authors.forename: Jiming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, Shanghai Medical College, Fudan University, Shanghai, China.|State Key Laboratory for Agro-Biotechnology, College of Biological Science, China Agricultural University, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology; D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000494:pharmacology; D006509:Hepatitis B / Q000097:blood / Q000276:immunology / Q000821:virology; D006514:Hepatitis B Surface Antigens / Q000276:immunology*; D017325:Hepatitis B Vaccines / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology*; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D007108:Immune Tolerance / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor