Interferon-α suppressed granulocyte colony stimulating factor production is reversed by CL097, A TLR7/8 agonist

National Liver Transplantation Unit, St. Vincent's University Hospital, Dublin, Ireland.
Journal of Gastroenterology and Hepatology (Impact Factor: 3.5). 12/2010; 25(12):1883-90. DOI: 10.1111/j.1440-1746.2010.06281.x
Source: PubMed


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.
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.
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.
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.

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