title: Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection.
abstract: BACKGROUND
  Altered functions of dendritic cells (DCs) and/or increases of regulatory T cells (Tregs) are involved in the pathogenesis of chronic hepatitis C virus (HCV) infection. A tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO), is reported to be an inducer of immune tolerance. Our aim was to clarify whether or not IDO is activated in chronic hepatitis C patients and its role in immune responses.
  
  
  METHODS
  This study enrolled 176 patients with chronic HCV infection and 37 healthy volunteers. Serum kynurenine concentration was evaluated by high-performance liquid chromatography, and its correlation with clinical parameters was examined. Monocyte-derived DCs were prepared from the subjects and subsequently stimulated with a combination of lipopolysaccharide and interferon-gamma to induce functional IDO (defined as IDO-DCs). The phenotypes, kynurenine or cytokine production, and T-cell responses with IDO-DCs were compared between the patients and healthy volunteers.
  
  
  RESULTS
  The serum kynurenine level in the patients was significantly higher than that in the healthy volunteers, and the level of serum kynurenine was positively correlated with the histological activity or fibrosis score. IDO activity in IDO-DCs from the patients was significantly higher than that in IDO-DCs from the volunteers. Furthermore, IDO-DCs from the patients induced more Tregs in vitro compared with those from the volunteers, and the frequency of induced Tregs by IDO-DCs was decreased with an IDO-specific inhibitor.
  
  
  CONCLUSIONS
  Systemic IDO activity is enhanced in chronic hepatitis C patients in correlation with the degree of liver inflammation and fibrosis. In response to inflammatory stimuli, DCs from the patients tend to induce Tregs, with some of this action being dependent on IDO.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
authors.forename: Koyo
authors.initials: K
authors.lastname: Higashitani
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Shoko
authors.initials: S
authors.lastname: Kuroda
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Yoshio
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Matsubara
authors.forename: Naruyasu
authors.initials: N
authors.lastname: Kakita
authors.forename: Tsugiko
authors.initials: T
authors.lastname: Oze
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sakakibara
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Eiji
authors.initials: E
authors.lastname: Mita
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Imai
authors.forename: Akinori
authors.initials: A
authors.lastname: Kasahara
authors.forename: Alato
authors.initials: A
authors.lastname: Okuno
authors.forename: Osamu
authors.initials: O
authors.lastname: Takikawa
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000328:Adult; D003713:Dendritic Cells / Q000201:enzymology*; D005260:Female; D019698:Hepatitis C, Chronic / Q000201:enzymology* / Q000276:immunology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase