Immunostimulatory Sequences Regulate Interferon-inducible Genes but not Allergic Airway Responses
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RATIONALE: 1018 ISS is a synthetic oligonucleotide containing immunostimulatory CpG motifs. In animal studies, 1018 ISS effectively inhibited Th2-mediated lung inflammation, including eosinophil infiltration, and airway hyperresponsiveness. OBJECTIVES: To evaluate whether 1018 ISS has activity in subjects with allergic asthma. METHODS: Forty subjects (n = 21, 1018 ISS; n = 19, placebo) were enrolled in a randomized, double-blind, placebo-controlled, parallel-group study to examine safety, pharmacologic activity, and efficacy of 1018 ISS on allergen-induced airway responses. Subjects received 36 mg of 1018 ISS or placebo by nebulization weekly for 4 wk. MEASUREMENTS: Allergen inhalation challenge was performed 24 h after the 2nd and 4th doses to measure the early and late fall in FEV(1). Sputum cells and peripheral blood mononuclear cells were collected before and after dosing, and gene expression was measured by quantitative polymerase chain reaction. MAIN RESULTS: Treatment with 1018 ISS significantly increased expression of interferon (IFN)-gamma and IFN-inducible genes, such as IFN-gamma-inducible 10 kD protein (IP10), monokine induced by IFN-gamma (MIG), IFN-stimulated gene (ISG)-54, monocyte chemotactic protein (MCP)-1, and MCP-2 from cells collected postdose (p < 0.05). There was no attenuation of the early or late decrease in FEV(1) after 1018 ISS compared with placebo, nor a reduction in allergen-induced sputum eosinophils or Th2-related gene expression measured in sputum cells. CONCLUSIONS: This study demonstrated that 1018 ISS is safe and pharmacologically active in the respiratory tract of asthmatics but, at this dose regimen, did not inhibit a fall in FEV(1) or other key features of the response to inhaled allergen challenge. This suggests that induction of IFN and IFN-inducible genes alone is not sufficient to inhibit allergen-induced responses in asthmatic subjects.
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