title: Innate immune tolerance and the role of kupffer cells in differential responses to interferon therapy among patients with HCV genotype 1 infection.
abstract: OBJECTIVE
  In patients with hepatitis C virus (HCV) infection, interferon alfa (IFN-α) alters expression of IFN-stimulated genes (ISGs), but little is understood about factors that determine outcomes of therapy. We used a systems biology approach to evaluate the acute response of patients with chronic hepatitis C to IFN-α therapy.
  
  
  METHODS
  We collected liver biopsy samples from 8 treatment-naïve patients with chronic HCV genotype 1 infection at baseline and 24 hours after treatment with IFN-α-2a (10 MU subcutaneously). Blood samples were collected before and up to 48 hours after administration of IFN-α-2a to measure HCV RNA levels and for gene expression analysis. Patients then received pegylated IFN-α-2a and ribavirin on day 5 of the study; therapy continued for up to 48 weeks.
  
  
  RESULTS
  Based on the kinetics of HCV RNA during the first 12 weeks of therapy, 2 patients were rapid virologic responders, 4 were early virologic responders, and 2 did not respond to therapy (nonresponders). Nonresponders had high pretreatment levels of ISG expression in the liver but not in peripheral blood mononuclear cells. In responders, after administration of IFN-α, intrahepatic ISG expression increased significantly from baseline and was associated with a rapid phase 1 decrease in HCV. We identified distinct hepatic expression and tissue distribution patterns of ISGs that segregated with treatment outcome. Importantly, Kupffer cells were a local source of IFN that promoted basal expression of ISG in hepatocytes of nonresponders. This finding was validated in cultured THP1 human macrophages that expressed IFN-β after exposure to viable HCV 2a. When Huh7 K2040 and Huh7 L2198S hepatoma cells were incubated with IFN-α-2a, expression of ISGs peaked by 4 hours and decreased by 72 hours, associated with an increase in level of HCV RNA. This indicates that constitutive exposure to IFN causes hepatoma cells to become tolerant of ISG function.
  
  
  CONCLUSIONS
  In patients with chronic HCV infection, IFN production by Kupffer cells might promote innate immune tolerance, characterized by a lack of response to IFN therapy. Strategies to disrupt the virus-host interactions that induce innate immune tolerance should improve therapy.
authors.affiliation: Liver Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address: dlau@bidmc.harvard.edu.
authors.forename: Daryl T-Y
authors.initials: DT
authors.lastname: Lau
authors.affiliation: Center for the Study of Hepatitis C Virus Infection and Immunity, Department of Immunology, University of Washington, Seattle, Washington.
authors.forename: Amina
authors.initials: A
authors.lastname: Negash
authors.affiliation: Liver Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Center for the Study of Hepatitis C Virus Infection and Immunity, Department of Immunology, University of Washington, Seattle, Washington.
authors.forename: Nanette
authors.initials: N
authors.lastname: Crochet
authors.affiliation: Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, Texas; Institute of Translational Science, University of Texas Medical Branch at Galveston, Galveston, Texas.
authors.forename: Mala
authors.initials: M
authors.lastname: Sinha
authors.affiliation: Liver Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Theoretical Biology & Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Guedj
authors.affiliation: Liver Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sharon
authors.initials: S
authors.lastname: Holder
authors.affiliation: Center for the Study of Hepatitis C Virus Infection and Immunity, Department of Immunology, University of Washington, Seattle, Washington.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Lemon
authors.affiliation: Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, Texas; Institute of Translational Science, University of Texas Medical Branch at Galveston, Galveston, Texas.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Luxon
authors.affiliation: Theoretical Biology & Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
authors.affiliation: Center for the Study of Hepatitis C Virus Infection and Immunity, Department of Immunology, University of Washington, Seattle, Washington.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
mesh_terms: D000328:Adult; D001706:Biopsy; D002478:Cells, Cultured; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D012367:RNA, Viral / Q000235:genetics*; D011994:Recombinant Proteins / Q000627:therapeutic use; D019562:Viral Load; D055815:Young Adult
chemical_list: D050835:Interferon Regulatory Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins