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

Abstract

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.

• Authors: Pierre-Olivier Fiset, Abdelilah Soussi-Gounni, Pota Christodoulopoulos, Meri Tulic, Steven E Sobol, Saul Frenkiel, François Lavigne, Bouchaib Lamkhioued, Qutayba Hamid
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 111 Issue 3 Pg. 580-6 (Mar 2003) ISSN: 0091-6749 [Print] United States
• PMID: 12642840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• CCL11 protein, human
• Chemokine CCL11
• Chemokines, CC
• Oligonucleotides, Antisense
• Protein Isoforms
• RNA, Messenger
• Thionucleotides
• Interleukin-4
• Immunoglobulin E
• Interferon-gamma

Topics

• Allergens (immunology)
• Chemokine CCL11
• Chemokines, CC (antagonists & inhibitors)
• Humans
• Hypersensitivity (physiopathology)
• Immunoglobulin E (genetics)
• Interferon-gamma (metabolism)
• Interleukin-4 (antagonists & inhibitors, genetics)
• Nasal Mucosa (drug effects, physiopathology)
• Oligonucleotides, Antisense (pharmacology)
• Protein Isoforms (genetics)
• RNA, Messenger (antagonists & inhibitors, biosynthesis)
• Thionucleotides (pharmacology)