title: A non-peptide CCR5 antagonist inhibits collagen-induced arthritis by modulating T cell migration without affecting anti-collagen T cell responses.
abstract: The chemokine receptors CCR5 and CXCR3 have been implicated as playing a central role in directing a Th1 inflammatory response. Here, we investigated whether a synthetic CCR5 antagonist affects the process of T cell migration to sites of inflammation. Immunization of DBA/1 mice with type II collagen resulted in typical arthritis, which is associated with cellular infiltration. Treatment with a CCR5 antagonist strikingly affected the development of arthritis by reducing both incidence and severity of disease. There was no substantial difference between collagen-immunized mice with and without antagonist treatment in the induction of anti-collagen T cell responses and the capacity to produce IL-12. This endogenous IL-12 functioned to induce comparable levels of CCR5 in these two immunized groups of T cells. Whereas a massive infiltration of inflammatory cells including CCR5(+) T cells occurred in the joints of mice immunized without antagonist, cellular infiltration in the antagonist-treated group was only marginal. These results indicate that administration of a CCR5 antagonist inhibits the development of arthritis not by affecting the generation of collagen-sensitized T cells but by interfering with their migration to joint lesions.
authors.affiliation: Department of Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yi-Fu
authors.initials: YF
authors.lastname: Yang
authors.forename: Takao
authors.initials: T
authors.lastname: Mukai
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Nobuya
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Shiro
authors.initials: S
authors.lastname: Ono
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Obika
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imanishi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsujimura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hamaoka
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000577:Amides / Q000627:therapeutic use*; D000818:Animals; D000917:Antibody Formation; D001168:Arthritis / Q000517:prevention & control*; D065100:CCR5 Receptor Antagonists; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000276:immunology*; D018664:Interleukin-12 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D000644:Quaternary Ammonium Compounds / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000502:physiology
chemical_list: D000577:Amides; D065100:CCR5 Receptor Antagonists; D000644:Quaternary Ammonium Compounds; D018664:Interleukin-12; D003094:Collagen; C119369:TAK 779