title: Suppressive effects of a novel CC chemokine receptor 4 antagonist on Th2 cell trafficking in ligand- and antigen-induced mouse models.
abstract: CC chemokine receptor 4 (CCR4) has been implicated as a preferential marker for T helper type 2 (Th2) cells, and is believed to be involved in the pathology of allergic diseases by controlling Th2 cell trafficking into inflamed tissues. The objective of the study was to characterize the pharmacological properties of E0001-163, a novel CCR4 antagonist. E0001-163 was tested in both in vitro chemotaxis assays as well as in vivo mouse models of CCR4 ligand-induced air pouch and antigen-induced airway inflammation by utilizing in vitro-polarized Th2 cells. In vitro, E0001-163 inhibited migratory response of human Th2-polarized cells to CCL22, a CCR4 ligand, with an IC50 value of 11.9 nM. E0001-163 significantly suppressed CCL22-induced Th2 cell trafficking into mouse air pouch in a dose-dependent manner at doses of 3 and 10mg/kg, suggesting that E0001-163 has an inhibitory effect on CCR4-mediated T cell trafficking in vivo. In addition, E0001-163 partially decreased Th2 cell trafficking and the level of IL-4 in the lungs in Th2-tansferred and ovalbumin (OVA)-challenged mice. T cell trafficking involves multiple chemokine receptors both in acute and chronic phases, and our findings suggest that CCR4, together with other chemokine receptors, may be involved in Th2 cell trafficking under disease conditions.
authors.affiliation: Exploratory Research Laboratories, Ono Pharmaceutical Co. Ltd., 17-2, Wadai, Tsukuba, Ibaraki 300-4247, Japan. Electronic address: t.komiya@ono.co.jp.
authors.forename: Takaki
authors.initials: T
authors.lastname: Komiya
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takeda
authors.forename: Noriki
authors.initials: N
authors.lastname: Watanabe
authors.forename: Masamichi
authors.initials: M
authors.lastname: Imai
authors.forename: Masaya
authors.initials: M
authors.lastname: Kokubo
authors.forename: Natsuko
authors.initials: N
authors.lastname: Tokuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ochiai
authors.forename: Hiromu
authors.initials: H
authors.lastname: Habashita
authors.forename: Shiro
authors.initials: S
authors.lastname: Shibayama
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018926:Anti-Allergic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000941:Antigens / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D054422:Chemokine CCL22 / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000276:immunology*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013424:Sulfanilamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D000096926:Benzenesulfonamides
chemical_list: D018926:Anti-Allergic Agents; D000941:Antigens; D054422:Chemokine CCL22; D008024:Ligands; D010047:Ovalbumin; D054398:Receptors, CCR4; D013424:Sulfanilamides; C515355:Ccr4 protein, mouse; C000590658:E0001-163; D000096926:Benzenesulfonamides
keywords: Allergic disease; CCR4 antagonist; Chemokine; Chemokine receptor; Th2 cell trafficking