Tumor Necrosis Factor-Alpha Induced by Hepatitis B Virus Core Mediating the Immune Response for Hepatitis B Viral Clearance in Mice Model

Tzeng, Horng-Tay; Tsai, Hwei-Fang; Chyuan, I‐Tsu; Liao, Hua‐Fang; Chen, Chun‐Jen; Chen, Pei‐Jer; Hsu, Ping–I

doi:10.1371/journal.pone.0103008

Cited by 55 publications

(50 citation statements)

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“…34 TNF-a has been described as potentially having a potentially modulating effect on HBV gene expression 35,36 and as being a key immune effector in HBV clearance in a study of a panel of immune effector-deficient mouse strains. 16,37 As an innate cytokine, TNF-a causes iMATE formation, which facilitates the expansion of the cytotoxic T-lymphocyte population against HBV. 31 Clinically, blockage of TNF-a with anti-TNF has been widely used in many immune-mediated diseases, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis and psoriatic arthritis.…”

Section: Discussionmentioning

confidence: 99%

“…14 In addition, studies from TNF-a knockout mice have also demonstrated that lack of the effect of TNF-a would impair the CD8 1 T-cell response to HBV, leading to ineffectiveness of viral clearance. 15,16 These observations indicate that TNF-a is a crucial innate cytokine for clearing HBV and eliminating HBV viral load in the host immune response against HBV infection.…”

Section: Introductionmentioning

confidence: 94%

“…16 HBV clearance was determined by the mouse genetic background: this approach induced HBV persistence in C57BL/6 mice, but not in BALB/c mice. 26,27 We further investigated the role of TNF-a blockade during HBV infection when TNF-a was neutralized with the soluble TNF receptor, etanercept, in this mouse model.…”

Section: Tnf-a Blockade Impaired Hbv Clearance and Enhanced Tcell Exhmentioning

confidence: 99%

“…All these results were consistent with those of our previous study. 16 To further address the extent of TNF-a blockage therapy on HBV clearance and viral load, we investigated the dynamic change of the HBV viral load and T cell exhaustion phenotype under different dosages of etanercept in mice hydrodynamically injected with replicationcompetent HBV DNA. The results shown in Figure 1a demonstrated that TNF-a blockage therapy potently impairs HBV clearance and results in persistently maintained serum HBsAg and HBV DNA in a dose-dependent manner.…”

Section: Tnf-a Blockade Impaired Hbv Clearance and Enhanced Tcell Exhmentioning

confidence: 99%

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Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Chyuan

Tsai²,

Tzeng

et al. 2015

Cell Mol Immunol

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Hepatitis B virus (HBV) reactivation and recurrence are common in patients undergoing immunosuppression therapy. Tumor necrosis factor (TNF) blockage therapy is effective for the treatment of many autoimmune inflammatory diseases. However, the role of TNF-a blockage therapy in the innate and adaptive immune responses against HBV is still not clear. A detailed analysis of HBV infection under TNF-a blockage therapy is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV clearance and T-cell responses were analyzed in a HBV-transfected mouse model under anti-TNF blockage therapy. Our results demonstrated that under TNF-a blockage therapy, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose-and temporal-dependent manner. The impairment of HBV clearance under anti-TNF-a blockage therapy occurred at early time points after HBV infection. In addition, TNF-a blockade maintained a higher serum HBV viral load and increased the number of intrahepatic programmed cell death (PD)-1 high CD127 low exhausted T cells. Furthermore, TNF-a blockade abolished Toll-like receptor 9 (TLR9) ligand-induced facilitation of HBV viral clearance. Taken together, TNF-a blockade impairs HBV clearance and enhances viral load, and these effects depend on early administration after HBV infection. Our results here demonstrate that early TNF-a blockade reduces viral clearance and persistently maintains elevated HBV viral load in a mouse model, suggesting that HBV may reactivate during therapy with TNF-a-blocking agents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Tnf-a Blockade Impaired Hbv Clearance and Enhanced Tcell Exhmentioning

confidence: 99%

Section: Tnf-a Blockade Impaired Hbv Clearance and Enhanced Tcell Exhmentioning

confidence: 99%

See 2 more Smart Citations

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Chyuan

Tsai²,

Tzeng

et al. 2015

Cell Mol Immunol

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“…What is becoming clear is that immunosuppressive agents and particularly, biological agents, including anti-TNF therapy, can cause major flares in HBV-related disease, leading to morbidity and mortality (4,5). Animal models and particularly, immunocompetent mouse models of persistent HBV infection have been used to dissect host-pathogen interactions that influence infection outcomes (6)(7)(8). These animal models can be used to define host cell signaling and cell death pathways that contribute to the persistence or control of HBV infection.…”

mentioning

confidence: 99%

Cellular inhibitor of apoptosis proteins prevent clearance of hepatitis B virus

Ebert

Preston

Allison

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Hepatitis B virus (HBV) infection can result in a spectrum of outcomes from immune-mediated control to disease progression, cirrhosis, and liver cancer. The host molecular pathways that influence and contribute to these outcomes need to be defined. Using an immunocompetent mouse model of chronic HBV infection, we identified some of the host cellular and molecular factors that impact on infection outcomes. Here, we show that cellular inhibitor of apoptosis proteins (cIAPs) attenuate TNF signaling during hepatitis B infection, and they restrict the death of infected hepatocytes, thus allowing viral persistence. Animals with a liver-specific cIAP1 and total cIAP2 deficiency efficiently control HBV infection compared with WT mice. This phenotype was partly recapitulated in mice that were deficient in cIAP2 alone. These results indicate that antagonizing the function of cIAPs may promote the clearance of HBV infection.hepatitis B virus | cellular inhibitor of apoptosis proteins | cIAP1 | cIAP2 | TNF I t is estimated that 2 billion people currently living in the world have been infected with hepatitis B virus (HBV), and among these, 360 million people are chronic carriers (1). HBV causes 780,000 deaths each year and is responsible for 50% and 33% of deaths attributable to liver cancer and cirrhosis, respectively (2). The host factors and molecular pathways that impact on HBV disease and clinical outcomes are not well-understood (3). What is becoming clear is that immunosuppressive agents and particularly, biological agents, including anti-TNF therapy, can cause major flares in HBV-related disease, leading to morbidity and mortality (4, 5). Animal models and particularly, immunocompetent mouse models of persistent HBV infection have been used to dissect host-pathogen interactions that influence infection outcomes (6-8). These animal models can be used to define host cell signaling and cell death pathways that contribute to the persistence or control of HBV infection.We induced HBV infection in two mouse models to examine the relevance of host factors in controlling infection. In a model that mimics partial control of infection, we were able to determine the importance of host cell signaling pathways through the use of gene-targeted mice. By identifying the relevant host cell signaling molecules that impact on HBV clinical outcomes, it may be possible to develop therapeutics that target host cell pathways and alter the course of HBV-related disease. ResultsChronic HBV Infection Can Be Mimicked in a Mouse Model. We used a previously described method to induce HBV persistence in immunocompetent mice (6). A plasmid containing a 1.2 over length sequence of HBV genotype A was hydrodynamically injected into mice, but in contrast to the previously published protocol, we did not anesthetize animals. Using this modified technique, we did not observe any injection-associated mortality, and C57BL/6 mice showed persistently high serum HBV DNA levels over 8-12 wk (Fig. 1A). Eventually, HBV DNA levels fell in all animals along with t...

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Lymphocyte Antigen 6 Complex, Locus C+ Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice

Wei

et al. 2019

Hepatology

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To understand the mechanism(s) of age‐dependent outcomes of hepatitis B virus (HBV) infection in humans, we previously established an age‐related HBV mouse model in which 6‐week‐old (N6W) C3H/HeN mice exhibited virus tolerance whereas 12‐week‐old (N12W) counterparts presented virus clearance. By investigating the hepatic myeloid cell dynamics in mice of these two ages, we aim to identify factors associated with HBV clearance. C3H/HeN mice were transfected with an HBV plasmid by hydrodynamic injection. Serum HBV markers were monitored weekly. Hepatic leucocyte populations and their cytokine/chemokine productions were examined at baseline, day 3 (D3), day 7 (D7), and day 14 after injection. C‐C chemokine receptor type 2 (CCR2) antagonist and clodronate (CLD) were respectively administered to N12W and N6W mice to study the roles of lymphocyte antigen 6 complex, locus C (Ly6C)+ monocytes and Kupffer cells (KCs) in viral clearance. N12W mice had a significantly higher number of TNF‐α–secreting Ly6C+ monocytes and fewer IL‐10–secreting KCs at D3 in the liver than their younger N6W counterparts after HBV transfection. In addition, the elevated number of interferon‐γ+TNF‐α+ CD8+ T cells at D7 was only seen in the older cohort. The enhanced Ly6C+ monocyte induction in N12W mice resulted from elevated C‐C motif chemokine ligand 2 (CCL2) secretion by hepatocytes. CCR2 antagonist administration hampered Ly6C+ monocyte recruitment and degree of KC reduction and delayed HBV clearance in N12W animals. Depletion of KCs by CLD liposomes enhanced Ly6C+ monocyte recruitment and accelerated HBV clearance in N6W mice. Conclusions: Ly6C+ monocytes and KCs may, respectively, represent the resistance and tolerance arms of host defenses. These two cell types play an essential role in determining HBV clearance/tolerance. Manipulation of these cells is a promising avenue for immunotherapy of HBV‐related liver diseases.

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Tumor Necrosis Factor-Alpha Induced by Hepatitis B Virus Core Mediating the Immune Response for Hepatitis B Viral Clearance in Mice Model

Cited by 55 publications

References 38 publications

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Cellular inhibitor of apoptosis proteins prevent clearance of hepatitis B virus

Lymphocyte Antigen 6 Complex, Locus C+ Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice

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