Presentation: Successful treatment of steroid resistant asthma model by blocking CD28 signal ( World Allergy Congress)

Friday, 16 October 2015

Hall D1 Foyer (Floor 3) (Coex Convention Center)

Akio Mori, MD, PhD , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Satoshi Kouyama, MSc , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Miyako Yamaguchi , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Yo Iijima , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Akemi Abe-Ohtomo, PhD , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Hiroaki Hayashi, MD , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Kentaroh Watai, MD , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Chihiro Mitsui, MD , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Chiyako Oshikata, MD , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Kiyoshi Sekiya, MD , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Takahiro Tsuburai, MD, PhD , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Mamoru Ohtomo, MD , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Yuma Fukutomi, MD, PhD , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Masami Taniguchi, MD, PhD , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Takayuki Ohtomo, PhD , Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

Osamu Kaminuma, PhD , Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Rationale: To investigate the role of helper T (Th) cells in steroid resistant (SR) asthma, steroid sensitive (SS) and resistant (SR) Th clones were selected in vitro, and then adoptively transferred into unprimed mice. Effect of CTLA4-Ig was analyzed both in vitro and in vivo.

Methods: For in vitro evaluation, ovalbumin (OVA) reactive Th clones were cultured with antigen presenting cells and OVA in the presence of various concentrations of dexamethasone (DEX). Proliferative responses of Th clones were measured by ³H-thymidine incorporation. For in vivo assessments, unprimed BALB/c mice were transferred with Th clones, challenged with OVA, and administered with DEX subcutaneously. Bronchoalveolar lavage fluid (BALF) was obtained 48 hr after challenge, and the number of infiltrating cells was differentially counted. CTLA4-Ig was administered through nasal inhalation or venous injection.

Results: SS and SR clones were selected based on the effect of DEX on the proliferative responses of antigen-stimulated Th clones. Airway infiltration of eosinophils and lymphocytes of mice transferred with SS clones were effectively inhibited by the administration of DEX. In contrast, those of mice transferred with SR clones were not significantly inhibited by DEX. Administration of CTLA4-Ig significantly suppressed the proliferation of DEX-treated SR clones in vitro, and the eosinophil infiltration of SR asthma model transferred with SR clones in vivo.

Conclusions: Steroid sensitivity of Th clones assessed in vitro was consistent with that of adoptively transferred asthma model assessed in vivo. Costimulatory signal mediated through CD28 is crucial for the induction of steroid resistance both in vitro and in vivo.

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