title: Ribavirin downmodulates inducible costimulator on CD4+ T cells and their interleukin-10 secretion to assist in hepatitis C virus clearance.
abstract: OBJECTIVE
  The immunological mechanism by which ribavirin (RBV) polarizes the T-helper (Th) 1/2 balance toward Th1 predominancy is not fully understood. We therefore examined whether RBV affects costimulatory signaling, which is known to be essential for regulating the Th1/2 balance.
  
  
  METHODS
  The expression of costimulatory molecules and their ligands, and levels of various cytokines, released from CD4(+) T cells obtained from healthy individuals or patients with chronic hepatitis C virus (HCV) infection were analyzed.
  
  
  RESULTS
  In CD4(+) T cells, RBV selectively downmodulates the expression of inducible costimulator (ICOS), a ligand for B7-H2 on dendritic cells, which mainly differentiates Th0 into Th2 cells. Moreover, the levels of interleukin-10 (IL-10) released from RBV-stimulated CD4(+) T cells also decreased, indicating that the downmodulation of ICOS induced by RBV might be correlated with the decrease in IL-10 released from Th cells, leading to the inhibition of Th2 activity. An analysis of the association between ICOS kinetics and hepatitis C virus (HCV) elimination in hepatitis C patients receiving combined pegylated interferon and RBV indicated that HCV elimination tended to occur more frequently in patients showing ICOS downmodulation with RBV treatment. A decrease in IL-10 production by CD4(+) T cells was also observed in association with ICOS downregulation in patients who succeeded in HCV elimination.
  
  
  CONCLUSIONS
  The downmodulation of ICOS in correlation with a reduction in IL-10 produced by CD4(+) T cells is possibly the immunological mechanism of action of RBV, which polarizes the Th1/2 balance toward a Th1 cytokine profile, thus contributing to the elimination of cells chronically infected with HCV.
authors.affiliation: Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Atsukawa
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Nakatsuka
authors.forename: Tamaki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Masumi
authors.initials: M
authors.lastname: Shimizu
authors.forename: Hideto
authors.initials: H
authors.lastname: Tamura
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Harimoto
authors.forename: Hidemi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Choitsu
authors.initials: C
authors.lastname: Sakamoto
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000187:drug effects / Q000378:metabolism*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000187:drug effects / Q000378:metabolism*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000494:pharmacology*; D015398:Signal Transduction; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D011092:Polyethylene Glycols; D012254:Ribavirin; D007371:Interferon-gamma; C417083:peginterferon alfa-2b