Modulation of allergic response in nasal mucosa by antisense oligodeoxynucleotides for IL-4.
BACKGROUND
The cytokine IL-4 is highly involved in T(H)2 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-gamma-producing cells were enumerated, and by using in situ hybridization, epsilon 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 epsilon 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-gamma 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.
Fiset
Pierre-Olivier
PO
Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.
Soussi-Gounni
Abdelilah
A
Christodoulopoulos
Pota
P
Tulic
Meri
M
Sobol
Steven E
SE
Frenkiel
Saul
S
Lavigne
François
F
Lamkhioued
Bouchaib
B
Hamid
Qutayba
Q
D000485:Allergens / Q000276:immunology; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000037:antagonists & inhibitors; D006801:Humans; D006967:Hypersensitivity / Q000503:physiopathology*; D007073:Immunoglobulin E / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000235:genetics*; D009297:Nasal Mucosa / Q000187:drug effects* / Q000503:physiopathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013873:Thionucleotides / Q000494:pharmacology
D000485:Allergens; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D012333:RNA, Messenger; D013873:Thionucleotides; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma