title: Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model.
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)-1(high)CD127(low) 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.
authors: 1] Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan, China [2] Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, China.
authors: I-Tsu
authors: IT
authors: Chyuan
authors: 1] Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, Taipei, Taiwan, China [2] Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, China.
authors: Hwei-Fang
authors: HF
authors: Tsai
authors: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China.
authors: Horng-Tay
authors: HT
authors: Tzeng
authors: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China.
authors: Chi-Chang
authors: CC
authors: Sung
authors: Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan, China.
authors: Chien-Sheng
authors: CS
authors: Wu
authors: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, China.
authors: Pei-Jer
authors: PJ
authors: Chen
authors: 1] Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China [2] Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, China.
authors: Ping-Ning
authors: PN
authors: Hsu
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000276:immunology*; D006509:Hepatitis B / Q000276:immunology* / Q000628:therapy; D006801:Humans; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D019562:Viral Load / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects
chemical_list: D019138:Antibodies, Blocking; D053699:Interleukin-7 Receptor alpha Subunit; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha