IL-12-based vaccination therapy reverses liver-induced systemic tolerance in a mouse model of hepatitis B virus carrier.
Liver-induced systemic immune tolerance that occurs during chronic hepadnavirus infection is the biggest obstacle for effective viral clearance. Immunotherapeutic reversal of this tolerance is a promising strategy in the clinic but remains to be explored. In this study, using a hepatitis B virus (HBV)-carrier mouse model, we report that IL-12-based vaccination therapy can efficiently reverse systemic tolerance toward HBV. HBV-carrier mice lost responsiveness to hepatitis B surface Ag (HBsAg) vaccination, and IL-12 alone could not reverse this liver-induced immune tolerance. However, after IL-12-based vaccination therapy, the majority of treated mice became HBsAg(-) in serum; hepatitis B core Ag was also undetectable in hepatocytes. HBV clearance was dependent on HBsAg vaccine-induced anti-HBV immunity. Further results showed that IL-12-based vaccination therapy strongly enhanced hepatic HBV-specific CD8(+) T cell responses, including proliferation and IFN-γ secretion. Systemic HBV-specific CD4(+) T cell responses were also restored in HBV-carrier mice, leading to the arousal of HBsAg-specific follicular Th-germinal center B cell responses and anti-hepatitis B surface Ag Ab production. Recovery of HBsAg-specific responses also correlated with both reduced CD4(+)Foxp3(+) regulatory T cell frequency and an enhanced capacity of effector T cells to overcome inhibition by regulatory T cells. In conclusion, IL-12-based vaccination therapy may reverse liver-induced immune tolerance toward HBV by restoring systemic HBV-specific CD4(+) T cell responses, eliciting robust hepatic HBV-specific CD8(+) T cell responses, and facilitating the generation of HBsAg-specific humoral immunity; thus, this therapy may become a viable approach to treating patients with chronic hepatitis B.
Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
Zhutian
Z
Zeng
Xiaohui
X
Kong
Fenglei
F
Li
Haiming
H
Wei
Rui
R
Sun
Zhigang
Z
Tian
D000818:Animals; D058070:Asymptomatic Diseases / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002353:Carrier State / Q000276:immunology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006509:Hepatitis B / Q000276:immunology / Q000517:prevention & control* / Q000635:transmission; D006510:Hepatitis B Antibodies / Q000097:blood; D006512:Hepatitis B Core Antigens / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000276:immunology; D017325:Hepatitis B Vaccines / Q000276:immunology / Q000627:therapeutic use*; D006515:Hepatitis B virus / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology; D007108:Immune Tolerance; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D008099:Liver / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019562:Viral Load / Q000187:drug effects / Q000276:immunology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D018664:Interleukin-12; D007371:Interferon-gamma