Effect of the hepatitis B virus S‑ecdCD40L vaccine therapy in HBV transgenic mice: A vaccine‑induced activation of antigen presenting dendritic cells

Guan,Huaqin; Lan,Songsong; Wu,Jinming; Tang,Binbin; Xu,Yin

doi:10.3892/mmr.2017.7322

Effect of the hepatitis B virus S‑ecdCD40L vaccine therapy in HBV transgenic mice: A vaccine‑induced activation of antigen presenting dendritic cells

Authors:
- Huaqin Guan
- Songsong Lan
- Jinming Wu
- Binbin Tang
- Yin Xu
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Affiliations: Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: August 22, 2017 https://doi.org/10.3892/mmr.2017.7322
Pages: 6102-6108

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Abstract

The classical hepatitis B virus (HBV) DNA vaccination plasmid only encodes for a single viral antigen, either the S or the PreS2/S antigen. Many strategies have been employed to improve the effect of these DNA vaccines. Our previous study identified that the fusion gene, HBV S‑ecd cluster of differentiation 40 ligand (CD40L), may promote the activation of dendritic cells (DCs) and enhance their function in vitro. In the current study, the effect of HBV S‑ecdCD40L vaccine therapy on liver DCs was investigated, and its therapeutic potential in HBV transgenic (HBV‑Tg) mice was evaluated. The eukaryotic expression plasmid, pcDNA3.1‑S‑ecdCD40L, was constructed by inserting the HBV S gene and mouse CD40L gene into the vector, pcDNA3.1 (+). HBV‑Tg mice were immunized with pcDNA3.1‑S‑ecdCD40L, pcDNA3.1‑S, pcDNA3.1 or PBS. Following this, immunophenotyping, cytokine production and T‑cell activation were analyzed in the CD11c‑enriched DC population obtained from the liver. Vaccine efficacy was further assessed by the detection of serological and biochemical parameters. When comparing with other control groups, DCs from HBV‑Tg mice immunized with pcDNA3.1‑S‑ecdCD40L exhibited increased expression of immunologically important cell molecules (CD86 and major histocompatibility complex class II), pro‑inflammatory cytokines (interleukin‑12), and enhanced capacity to promote allogeneic T‑cell proliferation. Furthermore, the HBV S‑ecdCD40L vaccine resulted in a significant inhibition of HBV DNA replication and downregulation of the hepatitis B virus surface antigen (HBsAg) in HBV‑Tg mice, without obvious liver injury. In conclusion, the HBV S‑ecdCD40L vaccine may be a feasible strategy for chronic HBV immunotherapy via promoting DC activation and function.

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1	European Association For The Study Of The Liver, . EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 57:167–185. 2012. View Article : Google Scholar : PubMed/NCBI
2	Buchmann P, Dembek C, Kuklick L, Jäger C, Tedjokusumo R, von Freyend MJ, Drebber U, Janowicz Z, Melber K and Protzer U: A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic mice. Vaccine. 31:1197–1203. 2013. View Article : Google Scholar : PubMed/NCBI
3	Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS, King AS, Herberg J, Gilson R, Alisa A, et al: The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med. 191:1269–1280. 2000. View Article : Google Scholar : PubMed/NCBI
4	Michel ML and Loirat D: DNA vaccines for prophylactic or therapeutic immunization against hepatitis B. Intervirology. 44:78–87. 2001. View Article : Google Scholar : PubMed/NCBI
5	Li X, Yang X, Jiang Y and Liu J: A novel HBV DNA vaccine based on T cell epitopes and its potential therapeutic effect in HBV transgenic mice. Int Immunol. 17:1293–1302. 2005. View Article : Google Scholar : PubMed/NCBI
6	Thermet A, Rollier C, Zoulim F, Trepo C and Cova L: Progress in DNA vaccine for prophylaxis and therapy of hepatitis B. Vaccine. 21:659–662. 2003. View Article : Google Scholar : PubMed/NCBI
7	Banchereau J and Steinman RM: Dendritic cells and the control of immunity. Nature. 392:245–252. 1998. View Article : Google Scholar : PubMed/NCBI
8	Beckebaum S, Cicinnati VR, Dworacki G, Müller-Berghaus J, Stolz D, Harnaha J, Whiteside TL, Thomson AW, Lu L, Fung JJ and Bonham CA: Reduction in the circulating pDC1/pDC2 ratio and impaired function of ex vivo-generated DC1 in chronic hepatitis B infection. Clin Immunol. 104:138–150. 2002. View Article : Google Scholar : PubMed/NCBI
9	Kakimi K, Isogawa M, Chung J, Sette A and Chisari FV: Immunogenicity and tolerogenicity of hepatitis B virus structural and nonstructural proteins: Implications for immunotherapy of persistent viral infections. J Virol. 76:8609–8620. 2002. View Article : Google Scholar : PubMed/NCBI
10	Van Kooten C and Banchereau J: CD40-CD40 ligand. J Leukoc Biol. 67:2–17. 2000.PubMed/NCBI
11	Grewal IS and Flavell RA: CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol. 16:111–135. 1998. View Article : Google Scholar : PubMed/NCBI
12	O'Sullivan B and Thomas R: CD40 and dendritic cell function. Crit Rev Immunol. 23:83–107. 2003. View Article : Google Scholar : PubMed/NCBI
13	Caux C, Massacrier C, Vanbervliet B, Dubois B, Van Kooten C, Durand I and Banchereau J: Activation of human dendritic cells through CD40 cross-linking. J Exp Med. 180:1263–1272. 1994. View Article : Google Scholar : PubMed/NCBI
14	Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A and Alber G: Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med. 184:747–752. 1996. View Article : Google Scholar : PubMed/NCBI
15	Wu JM, Lin XF, Huang ZM and Wu JS: Construction of the HBV S-ecdCD40L fusion gene and effects of HBV S-ecdCD40L modification on function of dendritic cells. J Viral Hepat. 18:e461–e467. 2011. View Article : Google Scholar : PubMed/NCBI
16	Lu L, Woo J, Rao AS, Li Y, Watkins SC, Qian S, Starzl TE, Demetris AJ and Thomson AW: Propagation of dendritic cell progenitors from normal mouse liver using granulocyte/macrophage colony-stimulating factor and their maturational development in the presence of type-1 collagen. J Exp Med. 179:1823–1834. 1994. View Article : Google Scholar : PubMed/NCBI
17	Gao W, Sun Y, Chen S, Zhang J, Kang J, Wang Y, Wang H, Xia G, Liu Q and Kang Y: Mushroom lectin enhanced immunogenicity of HBV DNA vaccine in C57BL/6 and HBsAg-transgenic mice. Vaccine. 31:2273–2280. 2013. View Article : Google Scholar : PubMed/NCBI
18	Lavanchy D: Hepatitis B virus epidemiology, disease burden, treatment and current, and emerging prevention and control measures. J Viral Hepat. 11:97–107. 2004. View Article : Google Scholar : PubMed/NCBI
19	Geng S, Zhong Y, Wang S, Liu H, Zou Q, Xie X, Li C, Yu Q, He Z and Wang B: Amiloride enhances antigen specific CTL by faciliting HBV DNA vaccine entry into cells. PLoS One. 7:e330152012. View Article : Google Scholar : PubMed/NCBI
20	Kosinska AD, Zhang E, Lu M and Roggendorf M: Therapeutic vaccination in chronic hepatitis B: Preclinical studies in the woodchuck. Hepat Res Treat. 2010:8175802010.PubMed/NCBI
21	Roy MJ, Wu MS, Barr LJ, Fuller JT, Tussey LG, Speller S, Culp J, Burkholder JK, Swain WF, Dixon RM, et al: Induction of antigen-specific CD8+ T cells, T helper cells, and protective levels of antibody in humans by particle-mediated administration of a hepatitis B virus DNA vaccine. Vaccine. 19:764–778. 2000. View Article : Google Scholar : PubMed/NCBI
22	Zhang Y, Su WJ, Wang J, Bai XF, Huang CX and Lian JQ: A fusion DNA vaccine encoding middle version of HBV envelope protein fused to interleukin-21 did not enhance HBV-specific immune response in mice. Viral Immunol. 27:430–437. 2014. View Article : Google Scholar : PubMed/NCBI
23	Yoon SK, Seo YB, Im SJ, Bae SH, Song MJ, You CR, Jang JW, Yang SH, Suh YS, Song JS, et al: Safety and immunogenicity of therapeutic DNA vaccine with antiviral drug in chronic HBV patients and its immunogenicity in mice. Liver Int. 35:805–815. 2015. View Article : Google Scholar : PubMed/NCBI
24	Mishra S, Lavelle BJ, Desrosiers J, Ardito MT, Terry F, Martin WD, De Groot AS and Gregory SH: Dendritic cell-mediated, DNA-based vaccination against hepatitis C induces the multi-epitope-specific response of humanized, HLA transgenic mice. PLoS One. 9:e1046062014. View Article : Google Scholar : PubMed/NCBI
25	Burgdorf S, Kautz A, Böhnert V, Knolle PA and Kurts C: Distinct pathways of antigen uptake and intracellular routing in CD4 and CD8 T cell activation. Science. 316:612–616. 2007. View Article : Google Scholar : PubMed/NCBI
26	Sato K and Fujita S: Dendritic cells: Nature and classification. Allergol Int. 56:183–191. 2007. View Article : Google Scholar : PubMed/NCBI
27	Zhang L, Tang Y, Akbulut H, Zelterman D, Linton PJ and Deisseroth AB: An adenoviral vector cancer vaccine that delivers a tumor-associated antigen/CD40-ligand fusion protein to dendritic cells. Proc Natl Acad Sci USA. 100:15101–15106. 2003; View Article : Google Scholar : PubMed/NCBI
28	Deisseroth A, Tang Y, Zhang L, Akbulut H and Habib N: TAA/ecdCD40L adenoviral prime-protein boost vaccine for cancer and infectious diseases. Cancer Gene Ther. 20:65–69. 2013. View Article : Google Scholar : PubMed/NCBI
29	Pillarisetty VG, Shah AB, Miller G, Bleier JI and DeMatteo RP: Liver dendritic cells are less immunogenic than spleen dendritic cells because of differences in subtype composition. J Immunol. 172:1009–1017. 2004. View Article : Google Scholar : PubMed/NCBI