title: Interferon-α suppressed granulocyte colony stimulating factor production is reversed by CL097, a TLR7/8 agonist.
abstract: OBJECTIVE
  Neutropenia, a major side-effect of interferon-α (IFN-α) therapy can be effectively treated by the recombinant form of granulocyte colony stimulating factor (G-CSF), an important growth factor for neutrophils. We hypothesized that IFN-α might suppress G-CSF production by peripheral blood mononuclear cells (PBMCs), contributing to the development of neutropenia, and that a toll-like receptor (TLR) agonist might overcome this suppression.
  
  
  METHODS
  Fifty-five patients who were receiving IFN-α/ribavirin combination therapy for chronic hepatitis C virus (HCV) infection were recruited. Absolute neutrophil counts (ANC), monocyte counts and treatment outcome data were recorded. G-CSF levels in the supernatants of PBMCs isolated from the patients and healthy controls were assessed by enzyme-linked immunosorbent assay following 18 h of culture in the absence or presence of IFN- α or the TLR7/8 agonist, CL097.
  
  
  RESULTS
  Therapeutic IFN-α caused a significant reduction in neutrophil counts in all patients, with 15 patients requiring therapeutic G-CSF. The reduction in ANC over the course of IFN-α treatment was paralleled by a decrease in the ability of PBMCs to produce G-CSF. In vitro G-CSF production by PBMCs was suppressed in the presence of IFN-α; however, co-incubation with a TLR7/8 agonist significantly enhanced G-CSF secretion by cells obtained both from HCV patients and healthy controls.
  
  
  CONCLUSIONS
  Suppressed G-CSF production in the presence of IFN-α may contribute to IFN-α-induced neutropenia. However, a TLR7/8 agonist elicits G-CSF secretion even in the presence of IFN-α, suggesting a possible therapeutic role for TLR agonists in treatment of IFN-α-induced neutropenia.
authors.affiliation: National Liver Transplantation Unit, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Tariq
authors.initials: T
authors.lastname: Tajuddin
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Ryan
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norris
authors.forename: John E
authors.initials: JE
authors.lastname: Hegarty
authors.forename: Cliona
authors.initials: C
authors.lastname: O'Farrelly
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D007494:Ireland; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D011804:Quinolines / Q000627:therapeutic use*; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use*; D013997:Time Factors; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; C547051:CL097 compound; D007093:Imidazoles; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011804:Quinolines; D011994:Recombinant Proteins; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a