Inhibition of antigen-induced eosinophilia and airway hyperresponsiveness by antisense oligonucleotides directed against the common beta chain of IL-3, IL-5, GM-CSF receptors in a rat model of allergic asthma.
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 (beta(c)). We hypothesized that blocking of this common beta(c) would impair the airway response to antigen. We report that an antisense (AS) phosphorothioate oligodeoxynucleotide (ODN) found to specifically inhibit transcription of the beta(c) in rat bone marrow cells also caused inhibition of beta(c) mRNA expression and of immunoreactive cells within the lungs of Brown Norway (BN) rats when injected intratracheally (p < 0.01). Inhibition of beta(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, beta(c) AS-ODN caused inhibition of antigen-induced airway hyperresponsiveness to leukotriene D4. Taken together, our findings demonstrate that the common beta(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 beta(c) for the treatment of asthma.
Allakhverdi
Zoulfia
Z
CHUM Research Center, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
Allam
Mustapha
M
Renzi
Paolo M
PM
D000818:Animals; D000941:Antigens / Q000276:immunology*; D001249:Asthma / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D001854:Bone Marrow Cells / Q000378:metabolism; D016535:Bronchial Hyperreactivity; D002452:Cell Count; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000473:pathology*; D007114:Immunization; D017998:Leukotriene D4 / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D018123:Receptors, Interleukin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016185:Receptors, Interleukin-3 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D053649:Receptors, Interleukin-5; D014158:Transcription, Genetic
D000941:Antigens; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D018123:Receptors, Interleukin; D016185:Receptors, Interleukin-3; D053649:Receptors, Interleukin-5; D017998:Leukotriene D4; D010047:Ovalbumin