title: Modulation of the IL-12/IFN-gamma axis by IFN-alpha therapy for hepatitis C.
abstract: Although IFN-alpha forms the foundation of therapy for chronic hepatitis C, only a minority of patients has a sustained response to IFN-alpha alone. The antiviral activities of IFN-alpha formed the rationale for its use in viral hepatitis. However, IFN-alpha and the other Type I IFNs are also pleiotropic immune regulators. Type I IFNs can promote IFN-gamma production by activating STAT4 but can also inhibit production of IL-12, a potent activator of STAT4 and IFN-gamma production. The efficacy of IFN-alpha in the treatment of hepatitis C may therefore depend in part on the balance of IFN-gamma-inducing and IL-12-suppressing effects. We characterized the effects of pegylated IFN-alpha therapy for hepatitis C on the capacity of patients' PBMC to produce IL-12 and IFN-gamma ex vivo. Cells from patients with a sustained virological response to therapy had significantly greater levels of IFN-alpha-driven IFN-gamma production prior to treatment than those from nonresponding patients. No differences in pretreatment IL-12 productive capacity were seen between patient groups. However, therapy with IFN-alpha led to suppression of inducible IL-12 production throughout the course of therapy in both groups of patients.
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Adriana A
authors.initials: AA
authors.lastname: Byrnes
authors.forename: Ding-You
authors.initials: DY
authors.lastname: Li
authors.forename: Kiwon
authors.initials: K
authors.lastname: Park
authors.forename: Douglas
authors.initials: D
authors.lastname: Thompson
authors.forename: Cathleen
authors.initials: C
authors.lastname: Mocilnikar
authors.forename: Parvathi
authors.initials: P
authors.lastname: Mohan
authors.forename: Jean P
authors.initials: JP
authors.lastname: Molleston
authors.forename: Michael
authors.initials: M
authors.lastname: Narkewicz
authors.forename: Huanfang
authors.initials: H
authors.lastname: Zhou
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Wolf
authors.forename: Kathleen B
authors.initials: KB
authors.lastname: Schwarz
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000627:therapeutic use; D016899:Interferon-beta / Q000008:administration & dosage / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D010865:Pilot Projects; D013329:Structure-Activity Relationship
chemical_list: D016898:Interferon-alpha; D018664:Interleukin-12; D016899:Interferon-beta; D007371:Interferon-gamma