Modulation of allergic response in nasal mucosa by antisense oligodeoxynucleotides for IL-4

Abstract

Background: The cytokine IL-4 is highly involved in TH2 inflammation, such as that seen in allergic rhinitis. IL-4 can induce IgE synthesis and eotaxin. Recent studies have shown that stimulation of allergic nasal tissue with ragweed allergen can induce local IL-4 mRNA production. Objective: We set out to determine whether IL-4 antisense phosphorothioate-modified oligodeoxynucleotides (PS-ODNs) could inhibit IL-4 production and downstream events of IL-4. Methods: Nasal mucosa biopsy specimens were obtained from patients with seasonal ragweed allergic rhinitis out of season, incubated ex vivo with or without PS-ODNs, and challenged with ragweed. FITC-labeled oligonucleotides were used to determine tissue uptake. By using immunocytochemistry, IL-4–, IL-13–, eotaxin 1–, and IFN-γ–producing cells were enumerated, and by using in situ hybridization, ϵ germline transcript RNA– and IL-4 mRNA–positive cells were examined. Results: The antisense PS-ODN was taken up by the tissue, and preincubation of the tissue with the IL-4 antisense PS-ODN caused a decrease in allergen-induced IL-4 mRNA and a decrease in the amount of IL-4 immunoreactivity (n = 7, P < .001). PS-ODNs had inhibitory effects on allergen-induced ϵ germline transcript RNA expression (n = 7, P < .001) and mucosa eotaxin 1 immunoreactivity (n = 7, P < .05). In contrast, the PS-ODNs increased the amount of IFN-γ immunoreactivity (n = 7, P < .05), suggesting a nonspecific mechanism for reduced synthesis of IgE and eotaxin. Conclusions: Our results show that the IL-4 antisense PS-ODN effectively inhibits IL-4, IgE synthesis, and eotaxin, principal mediators of allergic inflammation, suggesting that PS-ODNs might offer a possible topical treatment for allergic rhinitis. (J Allergy Clin Immunol 2003;111:580-6.)