title: Increased baseline proinflammatory cytokine production in chronic hepatitis C patients with rapid virological response to peginterferon plus ribavirin.
abstract: BACKGROUND
  Chronic hepatitis C (CHC) patients achieving rapid virological response (RVR) on PEG-IFN/ribavirin (P/R) therapy have high chance of sustained virological response (SVR). To analyze host immunological factors associated with RVR, viral kinetics, phenotype distribution and Th1/Th2 cytokine production by peripheral blood mononuclear cells (PBMC) were studied prior to and during P/R therapy.
  
  
  METHODS
  TNF-α, IFN-γ, IL-2, IL-6, IL-4 and IL-10 production by PBMC were measured after Toll-like receptor 4 (TLR-4) or phorbol myristate acetate/Ionomycin stimulation in 20 healthy controls and in 50 CHC patients before receiving and during P/R therapy. RVR was achieved by 14, complete early virological response (cEVR) by 19 patients and 17 patients were null-responders (NR).
  
  
  RESULTS
  Patients with RVR showed an increased baseline TNF-α and IL-6 production by TLR-4 activated monocytes and increased IFN-γ, decreased IL-4 and IL-10 production by lymphocytes compared to non-RVR patients. SVR was also associated with increased baseline TNF-α production and decreased IL-10 levels compared to patients who did not achieve SVR. Baseline IL-2 production was higher in cEVR compared to NR patients. Antiviral treatment increased TNF-α, IL-6 production by monocytes and IFN-γ secretion by lymphocytes and decreased IL-4 and IL-10 production by lymphocytes in cEVR compared to NR patients.
  
  
  CONCLUSIONS
  RVR was associated with increased baseline proinflammatory cytokine production by TLR-4 stimulated monocytes and by activated lymphocytes. In null-responders and in patients who did not achieve SVR both TLR-4 sensing function and proinflammatory cytokine production were impaired, suggesting that modulation of TLR activity and controlled induction of inflammatory cytokine production may provide further therapeutic strategy for CHC patients non-responding to P/R treatment.
authors.affiliation: Clinical Centre, First Department of Medicine, University of Pécs, Pécs, Hungary.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Par
authors.forename: Laszlo
authors.initials: L
authors.lastname: Szereday
authors.forename: Timea
authors.initials: T
authors.lastname: Berki
authors.forename: Laszlo
authors.initials: L
authors.lastname: Palinkas
authors.forename: Melinda
authors.initials: M
authors.lastname: Halasz
authors.forename: Attila
authors.initials: A
authors.lastname: Miseta
authors.forename: Geza
authors.initials: G
authors.lastname: Hegedus
authors.forename: Julia
authors.initials: J
authors.lastname: Szekeres-Bartho
authors.forename: Aron
authors.initials: A
authors.lastname: Vincze
authors.forename: Bela
authors.initials: B
authors.lastname: Hunyady
authors.forename: Alajos
authors.initials: A
authors.lastname: Par
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism* / Q000821:virology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D016898:Interferon-alpha / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012367:RNA, Viral / Q000097:blood; D012254:Ribavirin / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D018836:Inflammation Mediators; D016898:Interferon-alpha; D012367:RNA, Viral; D051197:Toll-Like Receptor 4; D012254:Ribavirin