Am. J. Respir. Crit. Care Med., Volume 165, Number 7, April 2002, 1015-1021

Inhibition of Antigen-induced Eosinophilia and Airway Hyperresponsiveness by Antisense Oligonucleotides Directed against the Common  Chain of IL-3, IL-5, GM-CSF Receptors in a Rat Model of Allergic Asthma

Zoulfia Allakhverdi, Mustapha Allam, and Paolo M. Renzi

CHUM Research Center, Notre-Dame Hospital, University of Montreal; Meakins-Christie Laboratories and Department of Medicine, McGill University, Montreal, Quebec, Canada

Airway obstruction, hyperresponsiveness, and the accumulation and persistence within the airways of inflammatory cells characterize asthma. Interleukin (IL)-3, granulocyte macrophage colony- stimulating factor (GM-CSF), and IL-5 are among several cytokines that have been shown to be increased in asthma and to contribute to atopic inflammation. They mediate their effect via receptors that have a common beta subunit (_c). We hypothesized that blocking of this common _c would impair the airway response to antigen. We report that an antisense (AS) phosphorothioate oligodeoxynucleotide (ODN) found to specifically inhibit transcription of the _c in rat bone marrow cells also caused inhibition of _c mRNA expression and of immunoreactive cells within the lungs of Brown Norway (BN) rats when injected intratracheally (p < 0.01). Inhibition of _c significantly reduced (p < 0.01) experimentally induced eosinophilia in vivo in ovalbumin (OVA)-sensitized BN rats after antigen challenge. Furthermore, when compared with mismatch-treated rats, _c AS-ODN caused inhibition of antigen-induced airway hyperresponsiveness to leukotriene D₄. Taken together, our findings demonstrate that the common _c of IL-3, IL-5, and GM-CSF receptors is involved in the eosinophil influx and airway hyperresponsiveness that follow OVA challenge and underscore the potential utility of a topical antisense approach targeting _c for the treatment of asthma.

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