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

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Cellular & Molecular Immunology 2015年第3期12卷 317-325页

作者： Hsu Chyuan Hwei-Fang Tsai Horng-Tay Tzeng Chi-Chang Sung Chien-Sheng Wu Pei-Jer Chen Ping-Ning Hsu Department of Internal Medicine Cathay General Hospital Taipei Taiwan China Department of Internal Medicine Taipei Medical University 5iquang HOHospital Taipei Taiwan China Institute of Clinical Medicine College of Medicine Taipei Medical University Taipei Taiwan China Graduate Institute ofImmunology College of Medicine National Taiwan University Taipei Taiwan China Department of Internal Medicine Far Eastern Memorial Hospital NewTaipei City Taiwan China Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan China Departmentof Internal Medicine National Taiwan University Hospital Taipei Taiwan China These authors contributed equally to this work.

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）- 1highCD127low 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 theraoy with TNF-a-blocking agents.

关键词： hbv viral load hepatitis B virus tumor necrosis factor

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