title: Selective down-regulation of Th2 cell-mediated airway inflammation in mice by pharmacological intervention of CCR4.
abstract: 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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Allergy and Immunology, The Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan. kaminuma-os@igakuken.or.jp
authors.forename: O
authors.initials: O
authors.lastname: Kaminuma
authors.forename: T
authors.initials: T
authors.lastname: Ohtomo
authors.forename: A
authors.initials: A
authors.lastname: Mori
authors.forename: D
authors.initials: D
authors.lastname: Nagakubo
authors.forename: K
authors.initials: K
authors.lastname: Hieshima
authors.forename: Y
authors.initials: Y
authors.lastname: Ohmachi
authors.forename: Y
authors.initials: Y
authors.lastname: Noda
authors.forename: K
authors.initials: K
authors.lastname: Katayama
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Motoi
authors.forename: N
authors.initials: N
authors.lastname: Kitamura
authors.forename: M
authors.initials: M
authors.lastname: Saeki
authors.forename: T
authors.initials: T
authors.lastname: Nishimura
authors.forename: O
authors.initials: O
authors.lastname: Yoshie
authors.forename: T
authors.initials: T
authors.lastname: Hiroi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D020397:Goblet Cells / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D054399:Receptors, CCR6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: C498126:CCR6 protein, mouse; C515355:Ccr4 protein, mouse; D054398:Receptors, CCR4; D054399:Receptors, CCR6