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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

Cellular & Molecular Immunology volume 13, pages 850–861 (2016)Cite this article

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.

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Acknowledgements

This work was supported in part by the MOST National 863 Project of China (2012AA02A407) and the National Science and Technology Major Program of Infectious Diseases (2013ZX10002001) to Bin Wang. We thank Dr. Douglas Lowrie for his editing and proofreading of the manuscript. We also thank Dr. Jane Q.L. Yu, Mr. Zhonghuai He, and Mr. Xianghua Shi for their assistance with this work.

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  1. 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: bwang3@fudan.edu.cn

Authors and Affiliations

  1. Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, Shanghai Medical College, Fudan University, Shanghai, China

    Xianzheng Wang, Haili Mi & Bin Wang

  2. NCPC New Drug R&D Co., Ltd., Shijiazhuang, China

    Aihua Dong & Xingjun Zhou

  3. Medical Center of Diagnostics and Treatment for Cervical Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China

    Jingjing Xiao

  4. State Key Laboratory for Agro-Biotechnology, College of Biological Science, China Agricultural University, Beijing, China

    Hanqian Xu & Bin Wang

  5. Department of Infectious Disease, Huashang Hospital, Fudan University, Shanghai, China

    Jiming Zhang

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Wang, X., Dong, A., Xiao, J. et al. 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. Cell Mol Immunol 13, 850–861 (2016). https://doi.org/10.1038/cmi.2015.64

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