Control of T cell-dependent steroid-resistant asthma model by several kinase inhibitors

A Mori,T Ohtomo,M Iwata,S Kouyama,Y Hamada,Y Nakamura,O Kaminuma,K Nagayama,I Yamaguchi,N Fujita,Y Kamide,Y Fukutomi,K Iwamoto,A Ohtomo-Abe,K Sekiya,K Yano,K Ryu,K Watai

doi:10.1183/13993003.congress-2022.327

Abstract

Background: To control therapy-resistant eosinophilia, synergistic effects of CTLA4-Ig, glucocorticoid, and several tyrosine kinase inhibitors (TKIs) on T cell-induced, steroid-resistant asthma model were investigated. Methods: Ovalbumin (OVA)-specific Th clones were established from DO11.10 transgenic mice expressing T cell receptor specific for OVA/H-2d. To analyze in vitro drug responsiveness, Th clones were cultured with antigen presenting cells and OVA in the presence of various concentrations of dexamethasone (DEX) and TKIs. Proliferative responses were measured by BrdU incorporation. For in vivo analysis, unprimed Balb/c mice were transferred with Th clones, challenged with OVA, and administered with DEX and TKIs subcutaneously. CTLA4-Ig was administered either intravenously or intranasally. BALF was obtained 48 hours after the challenge, and the number of infiltrating cells was differentially counted. Results: Steroid-sensitive (SS) and -resistant (SR) clones were selected based on in vitro effect of DEX on the proliferative responses of antigen-stimulated Th clones. Airway infiltration of eosinophils 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. Addition of CTLA4-Ig and several TKIs into the culture significantly suppressed the proliferation of DEX-treated SR clones in vitro. Administration of CTLA4-Ig and TKIs significantly suppressed eosinophil infiltration of SR asthma model transferred with SR clones in vivo. Conclusion: Costimulatory signal is a promising target of TKIs to treat steroid-resistant asthma.

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