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dc.contributor.authorTajuddin, Tariq*
dc.contributor.authorRyan, Elizabeth J*
dc.contributor.authorNorris, Suzanne*
dc.contributor.authorHegarty, John E*
dc.contributor.authorO'Farrelly, Cliona*
dc.date.accessioned2012-02-01T10:29:43Z
dc.date.available2012-02-01T10:29:43Z
dc.date.issued2012-02-01T10:29:43Z
dc.identifier.citationJ Gastroenterol Hepatol. 2010 Dec;25(12):1883-90. doi:, 10.1111/j.1440-1746.2010.06281.x.en_GB
dc.identifier.issn1440-1746 (Electronic)en_GB
dc.identifier.issn0815-9319 (Linking)en_GB
dc.identifier.pmid21092001en_GB
dc.identifier.doi10.1111/j.1440-1746.2010.06281.xen_GB
dc.identifier.urihttp://hdl.handle.net/10147/207505
dc.description.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.
dc.language.isoengen_GB
dc.subject.meshAdulten_GB
dc.subject.meshAgeden_GB
dc.subject.meshAntiviral Agents/*therapeutic useen_GB
dc.subject.meshCase-Control Studiesen_GB
dc.subject.meshCells, Cultureden_GB
dc.subject.meshDrug Therapy, Combinationen_GB
dc.subject.meshEnzyme-Linked Immunosorbent Assayen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshGranulocyte Colony-Stimulating Factor/*metabolismen_GB
dc.subject.meshHepatitis C, Chronic/*drug therapy/immunologyen_GB
dc.subject.meshHumansen_GB
dc.subject.meshImidazoles/*therapeutic useen_GB
dc.subject.meshInterferon-alpha/adverse effects/*therapeutic useen_GB
dc.subject.meshIrelanden_GB
dc.subject.meshLeukocyte Counten_GB
dc.subject.meshMaleen_GB
dc.subject.meshMiddle Ageden_GB
dc.subject.meshNeutropenia/chemically induced/*drug therapy/immunologyen_GB
dc.subject.meshNeutrophils/*drug effects/immunologyen_GB
dc.subject.meshPolyethylene Glycols/adverse effects/*therapeutic useen_GB
dc.subject.meshProspective Studiesen_GB
dc.subject.meshQuinolines/*therapeutic useen_GB
dc.subject.meshRecombinant Proteinsen_GB
dc.subject.meshRibavirin/*therapeutic useen_GB
dc.subject.meshTime Factorsen_GB
dc.subject.meshToll-Like Receptor 7/*agonistsen_GB
dc.subject.meshToll-Like Receptor 8/*agonistsen_GB
dc.subject.meshTreatment Outcomeen_GB
dc.titleInterferon-alpha suppressed granulocyte colony stimulating factor production is reversed by CL097, a TLR7/8 agonist.en_GB
dc.contributor.departmentNational Liver Transplantation Unit, St. Vincent's University Hospital, Dublin,, Ireland.en_GB
dc.identifier.journalJournal of gastroenterology and hepatologyen_GB
dc.description.provinceLeinster
html.description.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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