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

Cellular & Molecular Immunology volume 12, pages 317–325 (2015)Cite this article

Abstract

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-α blockage therapy in the innate and adaptive immune responses against HBV is still not clear. A detailed analysis of HBV infection under TNF-α 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-α 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-α blockage therapy occurred at early time points after HBV infection. In addition, TNF-α blockade maintained a higher serum HBV viral load and increased the number of intrahepatic programmed cell death (PD)-1highCD127low exhausted T cells. Furthermore, TNF-α blockade abolished Toll-like receptor 9 (TLR9) ligand-induced facilitation of HBV viral clearance. Taken together, TNF-α 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-α blockade reduces viral clearance and persistently maintains elevated HBV viral load in a mouse model, suggesting that HBV may reactivate during therapy with TNF-α-blocking agents.

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Acknowledgements

We thank Dr Shie-Liang Hsieh for critically reviewing the manuscript and Ms W-L Wang and Y-L Chen for assistance. This work was supported by grants from the National Science Council, Taiwan (NSC98-3112-B-002-047, NSC101-2320-B-038-019-, NSC 101-2321-B-002-008- and 102-2320-B-038 -040-MY3).

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Author notes

  1. I-Tsu Chyuan and Hwei-Fang Tsai: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan, China

    I-Tsu Chyuan

  2. Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, Taipei, Taiwan, China

    Hwei-Fang Tsai

  3. Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, China

    Hwei-Fang Tsai

  4. Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China

    Horng-Tay Tzeng, Chi-Chang Sung & Ping-Ning Hsu

  5. Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan, China

    Chien-Sheng Wu

  6. Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, China

    I-Tsu Chyuan & Pei-Jer Chen

  7. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, China

    Ping-Ning Hsu

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Correspondence to Ping-Ning Hsu.

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Chyuan, IT., Tsai, HF., Tzeng, HT. et al. Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model. Cell Mol Immunol 12, 317–325 (2015). https://doi.org/10.1038/cmi.2015.01

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