Cellular & Molecular Immunology (2016) 13, 850–861; doi:10.1038/cmi.2015.64; published online 13 July 2015 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 miceXianzheng Wang1, Aihua Dong2, Jingjing Xiao3, Xingjun Zhou2, Haili Mi1, Hanqian Xu4, Jiming Zhang5 and Bin Wang1,4 - 1Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, Shanghai Medical College, Fudan University, Shanghai, China
- 2NCPC New Drug R&D Co., Ltd., Shijiazhuang, China
- 3Medical Center of Diagnostics and Treatment for Cervical Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- 4State Key Laboratory for Agro-Biotechnology, College of Biological Science, China Agricultural University, Beijing, China
- 5Department of Infectious Disease, Huashang Hospital, Fudan University, Shanghai, China
Correspondence: Dr. B Wang, Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, Shanghai Medical College, Fudan University, Shanghai, China. E-mail: [email protected] Received 26 February 2015; Revised 6 June 2015; Accepted 6 June 2015
Advance online publication 13 July 2015
Top of pageAbstractGranulocyte-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. Keywords: adjuvant; chronic hepatitis B; GM-CSF; immune-tolerance; therapeutic vaccine
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发表于 2016-11-7 23:04
