Reversal of hepatitis <scp>B</scp> virus‐induced systemic immune tolerance by intrinsic innate immune stimulation

Han, Qiuju; Lan, Peixiang; Zhang, Jian; Zhang, Cai; Tian, Zhigang

doi:10.1111/jgh.12034

Cited by 15 publications

(12 citation statements)

References 42 publications

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“…Similarly, TLR7 was also analysed at multiple levels and has been found to be down‐regulated. It has been well documented across the world that HBV induces immune tolerance upon infection . Increasing studies have shown that the HBV infection impedes PRR‐mediated antiviral signalling in hepatocytes .…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, TLR7 was also analysed at multiple levels and has been found to be down-regulated. It has been well documented across the world that HBV induces immune tolerance upon infection [34]. Increasing studies have shown that the HBV infection impedes PRR-mediated HBV DNA was isolated from the culture media of transfected cells at respective time points, and the load was assessed by an absolute real-time PCR using WHO standards.…”

Section: Discussionmentioning

confidence: 99%

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Expression of microRNA‐155 correlates positively with the expression of Toll‐like receptor 7 and modulates hepatitis B virus via C/EBP‐β in hepatocytes

Sarkar

Panigrahi

Pal

et al. 2015

Journal of Viral Hepatitis

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Effective recognition of viral infection and successive activation of antiviral innate immune responses are vital for host antiviral defence, which largely depends on multiple regulators, including Toll-like receptors (TLRs) and microRNAs. Several early reports suggest that specific TLR-mediated immune responses can control hepatitis B virus (HBV) replication and express differentially with disease outcome. Considering the versatile function of miR-155 in the TLR-mediated innate immune response, we aimed to study the association between miR-155 and TLRs and their subsequent impact on HBV replication using both a HBV-replicating stable cell line (HepG2.2.15) and HBV-infected liver biopsy and serum samples. Our results showed that miR-155 was suppressed during HBV infection and a subsequent positive correlation of miR-155 with TLR7 activation was noted. Further, ectopic expression of miR-155 in vitro reduced HBV load as evidenced from reduced viral DNA, mRNA and subsequently reduced level of secreted viral antigens (HBsAg and HBeAg). Our results further suggested that CCAAT/enhancer-binding protein-β (C/EBP-β), a positive regulator of HBV transcription, was inhibited by miR-155. Taken together, our study established a correlation between miR-155 and TLR7 during HBV infection and also demonstrated in vitro that increased miR-155 level could help to reduce HBV viral load by targeting C/EBP-β.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Expression of microRNA‐155 correlates positively with the expression of Toll‐like receptor 7 and modulates hepatitis B virus via C/EBP‐β in hepatocytes

Sarkar

Panigrahi

Pal

et al. 2015

Journal of Viral Hepatitis

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“…[30][31][32] The second mechanism is by the induction of inferior specific immune responses including deficiency of HBV-specific CTLs and low levels of antiviral cytokine production. 29,33,34 For a successful immunotherapeutic approach, one should aim to break and overcome both of these immune tolerance mechanisms to mount an effective counterattack. We propose that our protocol of sustained stimulation via three daily pretreatments with GM-CSF before HBV vaccination induced significantly higher levels of DC maturation compared to pre-treatment for one or two days, enabling DCs to present antigen more effectively to the adaptive immune system.…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Dong²,

Xiao

et al. 2015

Cell Mol Immunol

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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-c production, and cytotoxic T lymphocytes, were dramatically enhanced in the three-day GM-CSF pre-treated group. After adoptive transfers of CD8 1 T cells from immunized animals, antigen-specific CD8 1 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 & Molecular Immunology

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“…Although it elicits strong immunogenicity as a preventive vaccine in healthy people, the current HBsAg vaccines cannot induce antibody to hepatitis B surface antigen (anti‐HBs) for viral‐clearance in chronic hepatitis B (CHB) patients . High levels of viral antigens in circulation have been shown to induce host immune tolerance with impaired dendritic cell, natural killer, or T‐cell and B‐cell functions and thus contribute to HBV persistence . How to break or bypass immune tolerance and induce anti‐HBV immune responses is still a major challenge in the development of HBV therapeutic vaccines.…”

mentioning

confidence: 99%

“…(3) High levels of viral antigens in circulation have been shown to induce host immune tolerance with impaired dendritic cell, natural killer, or T-cell and B-cell functions and thus contribute to HBV persistence. (4)(5)(6)(7) How to break or bypass immune tolerance and induce anti-HBV immune responses is still a major challenge in the development of HBV therapeutic vaccines.…”

mentioning

confidence: 99%

Vaccines targeting preS1 domain overcome immune tolerance in hepatitis B virus carrier mice

et al. 2017

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Strong tolerance to HBV surface antigens limits the therapeutic effect of the conventional HBsAg vaccination in both preclinical animal models and patients with chronic hepatitis B (CHB) infection. In contrast, we observed that clinical CHB patients presented less immune tolerance to the preS1 domain of HBV large surface antigen. To study whether targeting the weak tolerance of preS1 region could improve therapy gain, we explored vaccination with the long peptide of preS1 domain for HBV virions clearance. Our study showed that this preS1-polypeptide rather than HBsAg vaccination induced robust immune responses in the HBV carrier mice. The anti-preS1 rapidly cleared HBV virions in vivo and blocked HBV infection to hepatocytes in vitro. Intriguingly, vaccination of preS1-polypeptide even reduced the tolerized status of HBsAg, opening a therapeutic window for the host to respond to the HBsAg vaccine. A sequential administration of antigenically distinct preS1-polypeptide and HBsAg vaccines in HBV carrier mice could finally induce HBsAg-HBsAb serological conversion and clear chronic HBV infection in the carrier mice. These results suggest that preS1 can function as a therapeutic vaccination for the control of CHB.

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Reversal of hepatitis B virus‐induced systemic immune tolerance by intrinsic innate immune stimulation

Cited by 15 publications

References 42 publications

Expression of microRNA‐155 correlates positively with the expression of Toll‐like receptor 7 and modulates hepatitis B virus via C/EBP‐β in hepatocytes

Expression of microRNA‐155 correlates positively with the expression of Toll‐like receptor 7 and modulates hepatitis B virus via C/EBP‐β in hepatocytes

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

Vaccines targeting preS1 domain overcome immune tolerance in hepatitis B virus carrier mice

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