IL-15 prevents allergic rhinitis through reactivation of antigen-specific CD8⁺ cells - 20/08/11

Doi : 10.1016/j.jaci.2006.02.018

Noriaki Aoi, MD ^a,^b, Tokuko Masuda, BS ^a, Daisuke Murakami, MD ^a, Toshiki Yajima, MD, PhD ^a, Hiroyuki Mizubuchi, MS ^a, Hisakata Yamada, MD, PhD ^a, Hideyuki Kawauchi, MD, PhD ^b, Yasunobu Yoshikai, MD, PhD ^a,^⁎
^a From the Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka
^b Department of Otorhinolaryngology, Shimane University, Izumo

Reprint requests: Yasunobu Yoshikai, MD, PhD, Division of Host Defense, Research Center of Prevention of Infectious Disease, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

Fukuoka and Izumo, Japan

Abstract

Background

Allergic rhinitis is one of the most common allergic inflammatory diseases characterized by a predominant T_H2 response with antigen-specific IgE synthesis. IL-15 plays important roles in activation and maintenance of memory CD8⁺T cells capable of producing IFN-γ, which regulates T_H2 responses.

Objective

To investigate the roles of endogenous IL-15 in allergic inflammation, we examined allergic rhinitis in IL-15 knockout (KO) mice sensitized with ovalbumin followed by intranasal rechallenge with ovalbumin.

Methods

IL-15KO mice were sensitized intraperitoneally with ovalbumin/complete Freund’s adjuvant on day 0 and ovalbumin/IFA on day 7, and then were intranasally challenged with ovalbumin on days 21, 22, 23, 24, and 25. Nasal symptoms and histologic changes were examined. IgE production and T_H2 responses were measured by ELISA. Purified CD8⁺T cells or recombinant IL-15 were administered into ovalbumin-sensitized mice.

Results

The levels of IgE production and T_H2 responses in IL-15KO mice were comparable to those in control mice after ovalbumin sensitization. However, sneezing, infiltration of eosinophils into the nasal mucosa, and T_H2 cytokine production were aggravated in ovalbumin-sensitized IL-15KO mice after intranasal challenge with ovalbumin. Adoptive transfer of CD8⁺ T cells from ovalbumin-sensitized mice suppressed the T_H2 responses in mice but not in IL-15KO mice. Administration of IL-15 with ovalbumin significantly prevented the development of allergic rhinitis in ovalbumin-sensitized mice.

Conclusion

We demonstrate with IL-15KO mice that endogenous IL-15 plays an important role in suppression of allergic rhinitis at effector phase. Intranasal administration of IL-15 is useful as a therapeutic approach to control allergic rhinitis.

Clinical implications

Intranasal administration of recombinant IL-15 might become new immunotherapy for allergic rhinitis.

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Key words : IL-15, allergic rhinitis, T_H2 cells, CD8⁺ T cells

Abbreviations used : CFA, KLH, KO, LN, NK, WT

Plan

Methods

Mice

Antibodies and reagents

Sensitization and challenge

Evaluation of nasal signs

Measurement of ovalbumin-specific IgE, IgG₁, and IgG_2a

Measurement of ovalbumin-specific cytokine production by CD4⁺ T cells from the spleen and cervical lymph nodes

Histologic examination

Transfer assays

Intranasal administration of exogenous IL-15

Statistical analysis

Results

IL-15KO mice showed aggravated allergic inflammation at the effector phase of allergic rhinitis

IL-15-dependent CD8⁺ T cells suppressed T_H2 response at the effector phase of allergic rhinitis

Exogenous IL-15 prevents allergic rhinitis in ovalbumin-sensitized WT mice

Discussion

Supported by a Grant-in-Aid for Scientific Research on Priority Areas, Japan Society for Promotion of Science, and grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology (Dr Yoshikai), the Yakult Bioscience Foundation (Dr Yoshikai), and the Uehara Memorial Foundation (Dr Yoshikai).
Disclosure of potential conflict of interest: The authors have declared they have no conflict of interest.