Interferon-alpha suppressed granulocyte colony stimulating factor production is reversed by CL097, a TLR7/8 agonist.
AffiliationNational Liver Transplantation Unit, St. Vincent's University Hospital, Dublin,, Ireland.
Antiviral Agents/*therapeutic use
Drug Therapy, Combination
Enzyme-Linked Immunosorbent Assay
Granulocyte Colony-Stimulating Factor/*metabolism
Hepatitis C, Chronic/*drug therapy/immunology
Interferon-alpha/adverse effects/*therapeutic use
Neutropenia/chemically induced/*drug therapy/immunology
Polyethylene Glycols/adverse effects/*therapeutic use
Toll-Like Receptor 7/*agonists
Toll-Like Receptor 8/*agonists
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CitationJ Gastroenterol Hepatol. 2010 Dec;25(12):1883-90. doi:, 10.1111/j.1440-1746.2010.06281.x.
JournalJournal of gastroenterology and hepatology
AbstractBACKGROUND AND AIM: Neutropenia, a major side-effect of interferon-alpha (IFN-alpha) 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-alpha 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-alpha/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- alpha or the TLR7/8 agonist, CL097. RESULTS: Therapeutic IFN-alpha 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-alpha 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-alpha; 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-alpha may contribute to IFN-alpha-induced neutropenia. However, a TLR7/8 agonist elicits G-CSF secretion even in the presence of IFN-alpha, suggesting a possible therapeutic role for TLR agonists in treatment of IFN-alpha-induced neutropenia.
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