Control of Steroid Responsiveness of Th Cells in Asthma
Monday, March 7, 2016
South Exhibit Hall H (Convention Center)
Akio Mori, MD, PhD, Satoshi Kouyama, MSc, Miyako Yamaguchi, Yo Iijima, Akemi Ohtomo-Abe, PhD, Arisa Kinoshita, Yosuke Kamide, Hiroaki Hayashi, MD, Kentaro Watai, MD, Chihiro Mitsui, MD, Chiyako Oshikata, MD, Kiyoshi Sekiya, MD, Takahiro Tsuburai, MD, PhD, Mamoru Ohtomo, MD, Yuma Fukutomi, MD, PhD, Masami Taniguchi, MD, PhD, Takayuki Ohtomo, PhD, Osamu Kaminuma, PhD
Rationale: To investigate the role of helper T (Th) cells in severe asthma, steroid responsiveness of Th cells was analyzed.

Methods: PBMC obtained from mild (steroid sensitive, SS), steroid dependent (SD), and steroid resistant (SR) asthmatics were stimulated with mitogens. Der f 2-specific Th clones were established and effects of glucocorticoids (GCs) on the proliferation and cytokine synthesis were analyzed. Steroid responsiveness of murine Th clones reactive to ovalbumin were analyzed. Unprimed BALB/c mice were transferred with these clones and then antigen challenged. Effect of GC on BALF eosinophilia was evaluated. CTLA4-Ig was administered through nasal inhalation or venous injection.

Results: IL-5 production by PBMC of SS asthmatics was significantly reduced after ICS administration, but that of SD asthma remained high. IC50 values for the suppression of cytokine synthesis and proliferation responses by dexamethasone was not different among SS, SD, or SR asthmatics. Addition of CD28 signal induced steroid resistance in IL-2 and PI-3 kinase dependent manner. Murine SS and SR Th clones were selected based on the steroid sensitivity of their proliferation responses in vitro. Airway infiltration of eosinophils and lymphocytes of mice transferred with SS clones were effectively inhibited by GC. In contrast, those of mice transferred with SR clones were not significantly inhibited. Administration of CTLA4-Ig significantly suppressed the proliferation of GC-treated SR clones in vitro, and the BALF eosinophilia of mice transferred with SR clones in vivo.

Conclusions: Costimulatory signal mediated through CD28 seems crucial for the induction of steroid resistance and might be a target for therapeutic intervention.