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.

Download full-text


Available from: Elizabeth Ryan
  • [Show abstract] [Hide abstract]
    ABSTRACT: Not Available
    No preview · Conference Paper · Feb 1989
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic hepatitis C virus (HCV) infection occurs in patients who fail to mount an effective T-cell response against the virus. One hypothesis for poor anti-viral immunity in these patients is that the virus impedes the immune response by disabling dendritic cells (DCs), cells that play a key role in pathogen recognition and initiation of adaptive immunity. Initial studies in the 1990s supported this hypothesis, as they clearly demonstrated that monocyte-derived DCs obtained from patients with chronic HCV infection displayed a reduced ability to stimulate lymphocyte proliferation. However, over the last 20 years, the situation has become more ambiguous. Many studies support the initial observation of a DC defect, while others using different patient cohorts or technologies have clearly demonstrated intact DC function in patients with chronic HCV. It is likely that the true situation lies somewhere in between. Just as there is a spectrum of disease in patients with chronic HCV, DCs obtained from different patients may display different properties. It is important to reconcile these divergent findings, as a clearer understanding of how the virus affects DC function will facilitate the development of immunotherapy and therapeutic vaccination strategies for patients with chronic HCV infection.
    Full-text · Article · Sep 2011 · Journal of Viral Hepatitis
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colony-stimulating factors (CSFs) are attractive adjunctive anti-infective therapies. Used to enhance innate host defenses against microbial pathogens, the myeloid CSFs increase absolute numbers of circulating innate immune effector cells by accelerating bone marrow production and maturation, or augment the function of those cells through diverse effects on chemotaxis, phagocytosis, and microbicidal functions. This article summarizes the evidence supporting the accepted clinical uses of the myeloid CSFs in patients with congenital or chemotherapy-induced neutropenia, and presents an overview of proposed and emerging uses of the CSFs for the prevention and treatment of infectious diseases in other immunosuppressed and immunocompetent patient populations.
    No preview · Article · Dec 2011 · Infectious disease clinics of North America
Show more