Effect of CCR4 antagonist on T cell‐mediated allergic airway inflammation in mice

The chemokine receptor CCR4 has been implicated in Th2‐related allergic disorders. However, it has recently been demonstrated that not only Th2 but also Th1 and Th17 cells are involved in the development of allergic inflammation. Therefore, the effect of a selective CCR4 antagonist, Compound 22, on murine airway inflammation models initiated by antigen‐specific helper T cell subsets was investigated. Th2 and Th17 cells but not Th1 cells differentiated from OVA‐specific naive DO11.10 T cells significantly expressed CCR4. However, a CCR4 ligand, CCL17, induced chemotactic responses in Th2 but not Th17 cells. Compound 22 selectively suppressed CCL17‐mediated chemotaxis of Th2 cells in vitro. In the lungs of mice separately transferred with these T cell subsets, Th1 and Th2 cells but not Th17 cells accumulated upon OVA challenge. Subsequently, massive infiltration of eosinophils was occurred in Th2‐transferred mice, whereas neutrophils preferentially migrated in Th1‐ and Th17‐transferred mice. The administration of Compound 22 as well as an anti‐CCL17 mAb significantly alleviated Th2 and eosinophil infiltration but not Th1‐ or Th17‐mediated responses. The resulting bronchial hyperresponsiveness but not goblet cell hyperplasia in Th2‐transferred mice was suppressed by Compound 22. Conclusively, CCR4 antagonists are promising drugs for the treatment of Th2 cell‐mediated allergic inflammatory diseases.