Immunocompetent nontransgenic mouse models for studying hepatitis <scp>B</scp> virus immune responses

Tzeng, Horng-Tay; Hsu, Ping–I; Chen, Pei‐Jer

doi:10.1111/jgh.12035

Cited by 9 publications

(5 citation statements)

References 39 publications

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“…Although we did not find detectable levels of IL-23 in the livers of HBV-carrier hosts, TLR-2 expression on Vg4 cells was enhanced (data not shown), which might relate to IL-17 expression. Because HBV cannot infect mice to best recapitulate the human disease, our HBV-carrier murine model has certain limitations-for instance, obvious hepatic lesions or detectable covalently closed circular DNA absent in these HBV-tolerant mice (36). However, these models can effectively replicate important aspects of HBVinduced tolerance (36), including persistent exposure to HBV Ags in the liver and the presence of exhausted hepatic HBV-specific CD8 + T cells with absence of inflammation.…”

Section: Gr1mentioning

confidence: 99%

“…Because HBV cannot infect mice to best recapitulate the human disease, our HBV-carrier murine model has certain limitations-for instance, obvious hepatic lesions or detectable covalently closed circular DNA absent in these HBV-tolerant mice (36). However, these models can effectively replicate important aspects of HBVinduced tolerance (36), including persistent exposure to HBV Ags in the liver and the presence of exhausted hepatic HBV-specific CD8 + T cells with absence of inflammation. Importantly, this model can mimic the immune-tolerant phase of young (children and young adult) chronic hepatitis B patients who reportedly still possess some HBV-specific T cells that display a partial profile of T cell exhaustion with a certain ability to proliferate and produce cytokines (37).…”

Section: Gr1mentioning

confidence: 99%

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γδT Cells Drive Myeloid-Derived Suppressor Cell–Mediated CD8+ T Cell Exhaustion in Hepatitis B Virus–Induced Immunotolerance

Kong

Sun

Chen

et al. 2014

The Journal of Immunology

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The mechanisms of liver hepatitis B virus (HBV)–induced systemic immune tolerance are still elusive, and the role of γδT cells has not yet been described. We examined the function of γδT cells in HBV-carrier mice––immunocompetent mice with plasmid-mediated persistent HBV expression in the liver. In this study, we found that γδT cell deficiency led to a break in HBV-induced tolerance and subsequent recovery of hepatic HBV-specific CD8+ T cells. Of interest, IL-17−/− mice phenocopied TCRδ−/− mice in terms of losing HBV persistence, and adoptive transfer of γδT cells restored HBV-persistent expression in TCRδ−/− mice. We further observed that hepatic CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) play a major role in this mechanism, as they were significantly reduced in both HBV-carrier TCRδ−/− and IL-17−/− mice. MDSC numbers also recovered after adoptive transfer of γδT cells, particularly Vγ4+ T cells. Furthermore, anti-Gr1–mediated MDSC depletion in HBV-carrier mice accelerated HBV elimination from the host, whereas MDSCs transferred to γδT cell-deficient mice restored HBV-induced tolerance. Accordingly, inhibition of MDSCs by the arginase-1 inhibitor norNOHA enhanced the number of HBV-specific CD8+ T cells and promoted HBV clearance. We also observed enhanced CD8+ T cell number with a notable decline of MDSCs in TCRδ−/− mice compared with wild-type mice during the recombinant adeno-associated virus/HBV1.3 virus infection. Importantly, HBV-carrier TCRδ−/− mice not only exhibited increased anti-HBV CD8+ T cells but also markedly reduced MDSCs. Overall, the current study reveals that γδT cells play a previously unrecognized regulatory role in liver tolerance by mobilizing MDSC infiltration to the liver, leading to MDSC-mediated CD8+ T cell exhaustion.

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Section: Gr1mentioning

confidence: 99%

Section: Gr1mentioning

confidence: 99%

γδT Cells Drive Myeloid-Derived Suppressor Cell–Mediated CD8+ T Cell Exhaustion in Hepatitis B Virus–Induced Immunotolerance

Kong

Sun

Chen

et al. 2014

The Journal of Immunology

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“…In this model, HBV genome is inserted to the genome of viral vectors, which initiates HBV replication and secretion of infectious HBV virions. Both vector models express HBV replication intermediates, and the dose of Ad-HBV directly correlates with the outcome of HBV persistence (52). AAV belongs to the family Parvoviridae, which is characterized by site-specific integration, natural deficiency, and low immunogenicity.…”

Section: Viral Vector-mediated Transfection Mouse Modelmentioning

confidence: 99%

“…Both Ad-HBV and AAV-HBV transfection mouse models can establish persistent HBV replication for more than 3 months or even more than 1 year (46,52,54). Notably, only low doses of Ad-HBV have been reported to establish such persistent HBV replication (46).…”

Section: Applications Of the Viral Vector-mediated Transfection Mouse Modelmentioning

confidence: 99%

In Vivo Mouse Models for Hepatitis B Virus Infection and Their Application

Broering

et al. 2021

Front. Immunol.

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Despite the availability of effective vaccination, hepatitis B virus (HBV) infection continues to be a major challenge worldwide. Research efforts are ongoing to find an effective cure for the estimated 250 million people chronically infected by HBV in recent years. The exceptionally limited host spectrum of HBV has limited the research progress. Thus, different HBV mouse models have been developed and used for studies on infection, immune responses, pathogenesis, and antiviral therapies. However, these mouse models have great limitations as no spread of HBV infection occurs in the mouse liver and no or only very mild hepatitis is present. Thus, the suitability of these mouse models for a given issue and the interpretation of the results need to be critically assessed. This review summarizes the currently available mouse models for HBV research, including hydrodynamic injection, viral vector-mediated transfection, recombinant covalently closed circular DNA (rc-cccDNA), transgenic, and liver humanized mouse models. We systematically discuss the characteristics of each model, with the main focus on hydrodynamic injection mouse model. The usefulness and limitations of each mouse model are discussed based on the published studies. This review summarizes the facts for considerations of the use and suitability of mouse model in future HBV studies.

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“…According to recent studies, OMT inhibited the replication of HBV and the expression of HBsAg and HBeAg in HepG2.2.15 cells and in transgenic mice13, 14. The HBV transgenic mice demonstrated limited production and expression of HBV antigens, but were enitally tolerant to HBV antigens15, 16. Due to the limited availability of appropriate experiment models, earlier studies failed to detect OMT-induced immune responses to HBV infection in normal subjects.…”

Section: Introductionmentioning

confidence: 99%

T cell--associated immunoregulation and antiviral effect of oxymatrine in hydrodynamic injection HBV mouse model

Sang

Han

Zhang

et al. 2017

Acta Pharmaceutica Sinica B

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Although oxymatrine (OMT) has been shown to directly inhibit the replication of hepatitis B virus (HBV) in vitro, limited research has been done with this drug in vivo. In the present study, the antiviral effect of OMT was investigated in an immunocompetent mouse model of chronic HBV infection. The infection was achieved by tail vein injection of a large volume of DNA solution. OMT (2.2, 6.7 and 20 mg/kg) was administered by daily intraperitoneal injection for 6 weeks. The efficacy of OMT was evaluated by the levels of HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B core antigen (HBcAg). The immunoregulatory activity of OMT was evaluated by serum ELISA and flow cytometry. Results shows that OMT at 20 mg/kg inhibited HBV replication, and it was more efficient than entecavir (ETV) in the elimination of serum HBsAg and intrahepatic HBcAg. In addition, OMT accelerated the production of interferon-γ (IFN-γ) in a dose-dependent manner in CD4+ T cells. Our findings demonstrate the beneficial effects of OMT on the enhancement of immunological function and in the control of HBV antigens. The findings suggest this drug to be a good antiviral therapeutic candidate for the treatment of HBV infection.

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Immunocompetent nontransgenic mouse models for studying hepatitis B virus immune responses

Cited by 9 publications

References 39 publications

γδT Cells Drive Myeloid-Derived Suppressor Cell–Mediated CD8+ T Cell Exhaustion in Hepatitis B Virus–Induced Immunotolerance

γδT Cells Drive Myeloid-Derived Suppressor Cell–Mediated CD8+ T Cell Exhaustion in Hepatitis B Virus–Induced Immunotolerance

In Vivo Mouse Models for Hepatitis B Virus Infection and Their Application

T cell--associated immunoregulation and antiviral effect of oxymatrine in hydrodynamic injection HBV mouse model

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