Activated intrahepatic antigen-presenting cells inhibit hepatitis B virus replication in the liver of transgenic mice.
In this study we evaluated the ability of activated intrahepatic APCs to inhibit hepatitis B virus (HBV) replication in transgenic mice. Intrahepatic APCs were activated by administration of an anti-CD40 agonistic mAb (alphaCD40). We showed that a single i.v. injection of alphaCD40 was sufficient to inhibit HBV replication noncytopathically by a process associated with the recruitment of dendritic cells, macrophages, T cells, and NK cells into the liver and the induction of inflammatory cytokines. The antiviral effect depended on the production of IL-12 and TNF-alpha by activated APCs; however, it was mediated primarily by IFN-gamma produced by NK cells, and possibly T cells, that were activated by IL-12. Collectively, these results suggest that activated APCs can directly produce antiviral cytokines (IL-12, TNF-alpha) and trigger the production of other cytokines (i.e., IFN-gamma) by other cells (e.g., NK cells and T cells) that do not express CD40. These results provide insight into a hitherto unsuspected antiviral function of intrahepatic APCs, and they suggest that therapeutic activation of APCs may represent a new strategy for the treatment of chronic HBV infection.
Kimura
Kiminori
K
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Kakimi
Kazuhiro
K
Wieland
Stefan
S
Guidotti
Luca G
LG
Chisari
Francis V
FV
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D000998:Antiviral Agents / Q000008:administration & dosage; D019013:CD40 Antigens / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology* / Q000502:physiology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology; D014779:Virus Replication / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D019013:CD40 Antigens; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma