title: Indoleamine-2,3-dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B.
abstract: Indoleamine-2, 3-dioxygenase (IDO), an interferon-γ-inducible enzyme catalyzing tryptophan into kynurenine, exerts dual functions in infectious diseases, acting as a suppressor of intracellular pathogens and as an immune regulator. We explored the roles of IDO in hepatitis B virus (HBV) clearance from infected patients. We examined IDO activity, serum chemokines, and cytokines in 53 HBV-positive patients (25 acute hepatitis, 14 chronic hepatitis, and 14 hepatic flare) and 14 healthy volunteers. In order to clarify the mechanisms of IDO induction and its impact on HBV replication, we used a culture model consisting of human natural killer cells, plasmacytoid dendritic cells, and HBV-transfected Huh7 cells in which IDO expression is controlled. A robust activation of IDO with an inverse correlation of alanine aminotransferase at the peak was observed in patients with acute hepatitis B but not in patients with hepatic flare. In acute hepatitis patients who eventually cleared HBV, IDO activity, chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, and CXCL11 increased at the peak of alanine aminotransferase. In contrast, in patients with hepatic flare, IDO activity remained at lower levels during the observation period, regardless of the surge of CXCL9, CXCL10, and CXCL11 at the alanine aminotransferase peak. Natural killer cells and plasmacytoid dendritic cells synergistically produced interferon-γ and interferon-α, thereby enhancing IDO activity and HBV suppression in Huh7 cells. Such suppressor capacity of IDO on HBV was abrogated in IDO-knockout cells and recovered by the reinduction of IDO in the cells.
  
  
  CONCLUSIONS
  IDO is an anti-HBV effector and an indicator of subsequent immune responses operative during the early phase of infection; its activity is boosted by coexisting natural killer cells and plasmacytoid dendritic cells.
authors.affiliation: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Yoshio
authors.affiliation: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Sugiyama
authors.affiliation: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Shoji
authors.affiliation: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mano
authors.affiliation: Department of Gastroenterology and Hepatology, National Hospital Organization, Osaka National Hospital, Chuo-ku, Osaka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Mita
authors.affiliation: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Matsuura
authors.affiliation: The National Center for Geriatrics and Gerontology, Aichi, Japan.
authors.forename: Alato
authors.initials: A
authors.lastname: Okuno
authors.affiliation: The National Center for Geriatrics and Gerontology, Aichi, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takikawa
authors.affiliation: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizokami
authors.affiliation: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
mesh_terms: D000208:Acute Disease; D000328:Adult; D015415:Biomarkers / Q000097:blood; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000097:blood; D005260:Female; D006509:Hepatitis B / Q000097:blood / Q000201:enzymology* / Q000276:immunology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000502:physiology*; D008297:Male; D008875:Middle Aged
chemical_list: D015415:Biomarkers; D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase