Therapeutic approach to steroid-resistant asthma

Abstract Background To control therapy-resistant eosinophilia, synergistic effects of CTLA4-Ig and glucocorticoid was investigated on T cell-induced asthma model. Methods Ovalbumin (OVA) specific murine helper T cell (Th) clones were established from DO11.10 transgenic mice. To analyze steroid responsiveness in vitro, Th clones were cultured with antigen presenting cells and OVA in the presence of various concentration of dexamethasone (DEX). Proliferative responses were measured by incorporation of either 3H-thymidine or BrdU. For in vivo analysis, unprimed Balb/c mice were transferred with Th clones, challenged with OVA, and administered with DEX subcutaneously. CTLA4-Ig was administered intravenously. 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 the 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 into the culture significantly suppressed the proliferation of DEX-treated SR clones in vitro. Administration of CTLA4-Ig significantly suppressed eosinophil infiltration of SR asthma model transferred with SR clones in vivo. CTLA4-Ig and DEX synergistically suppressed in vitro proliferation of SS clones and in vivo BALF eosinophilia of mice transferred with SS clones. Conclusion Blocking costimulatory signal mediated through CD28 is a promising target to treat therapy-resistant eosinophilia.