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Immunostimulatory Sequences Regulate Interferon-inducible Genes but not Allergic Airway Responses

McMaster University, Hamilton, Ontario; Hopital Laval, Quebec City, Quebec, Canada; and Dynavax Technologies, Berkeley, California

Correspondence and requests for reprints should be addressed to Paul O'Byrne, M.B., HSC 3W10, McMaster University, 1200 Main Street West, Hamilton, ON, Canada, L8N 3Z5. E-mail: obyrnep{at}mcmaster.ca

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 FEV₁. 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)- and IFN-inducible genes, such as IFN-–inducible 10 kD protein (IP10), monokine induced by IFN- (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 FEV₁ 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 FEV₁ 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.

Key Words: airway responses • allergen inhalation challenge • allergic asthma • gene expression, immunostimulatory CpG motifs

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