Selective down-regulation of Th2 cell-mediated airway inflammation in mice by pharmacological intervention of CCR4

• Published in: Clinical and experimental allergy 2012-02, Vol.42 (2), p.315-325
• Main Authors: Kaminuma, O., Ohtomo, T., Mori, A., Nagakubo, D., Hieshima, K., Ohmachi, Y., Noda, Y., Katayama, K., Suzuki, K., Motoi, Y., Kitamura, N., Saeki, M., Nishimura, T., Yoshie, O., Hiroi, T.
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; airway inflammation; Animal models; Animals; Antibodies; Biological and medical sciences; bronchial hyperresponsiveness; CCR6 protein; chemokine; Chemokine receptors; CXCR3 protein; Disease Models, Animal; Down-Regulation - drug effects; Down-Regulation - genetics; Down-Regulation - immunology; eosinophil; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Goblet cells; Goblet Cells - immunology; Goblet Cells - pathology; Helper cells; Hyperplasia; Hypersensitivity; Immune response (cell-mediated); Inflammation; Inflammation - drug therapy; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Lung; Lymphocytes T; Mice; Mice, Inbred BALB C; Mice, Knockout; Ovalbumin; Polarization; Receptors, CCR4 - antagonists & inhibitors; Receptors, CCR4 - genetics; Receptors, CCR4 - immunology; Receptors, CCR6 - antagonists & inhibitors; Receptors, CCR6 - genetics; Receptors, CCR6 - immunology; Respiratory Hypersensitivity - drug therapy; Respiratory Hypersensitivity - genetics; Respiratory Hypersensitivity - immunology; Respiratory Hypersensitivity - pathology; Respiratory tract diseases; T cell; Th1 Cells - immunology; Th1 Cells - pathology; Th17 Cells - immunology; Th17 Cells - pathology; Th2 Cells - immunology; Th2 Cells - pathology
• ISSN: 0954-7894; 1365-2222
• DOI: 10.1111/j.1365-2222.2011.03847.x

Summary Background The chemokine receptor CCR4 has been implicated in Th2 cell‐mediated immune responses. However, other T cell subsets are also known to participate in allergic inflammation. Objective The role of CCR4 in Th1, Th2, and Th17 cell‐mediated allergic airway inflammation was investigated. Method We generated an allergic airway inflammation model by adoptive transfer of in vitro‐polarized ovalbumin (OVA)‐specific Th1, Th2, and Th17 cells. The effect of a low‐molecular weight CCR4 antagonist, Compound 22, on this model was examined. Results Upon in vitro polarization of DO11.10 naïve T cells, Th1‐ and Th2‐polarized cells dominantly expressed CXCR3 and CCR4, respectively, while Th17‐polarized cells expressed CCR6 and CCR4. Intranasal OVA‐challenge of mice transferred with each T cell subset induced accumulation of T cells in the lungs. Eosinophils were also massively accumulated in Th2‐transferred mice, whereas neutrophils were preferentially recruited in Th1‐ and Th17‐transferred mice. Compound 22, as well as anti‐CCL17 or anti‐CCL22 antibody selectively suppressed accumulation of Th2 cells and eosinophils in the lungs of Th2‐transferred and OVA‐challenged mice. Compound 22 also inhibited bronchial hyperresponsiveness but had little effect on goblet cell hyperplasia in Th2‐transferred and OVA‐challenged mice. Conclusions and Clinical Relevance There were notable differences in allergic lung inflammation mediated by different T cell subsets. CCR4 blockage was selectively effective for suppression of Th2‐mediated allergic inflammation by blocking infiltration of Th2 cells.