A non-peptide CCR5 antagonist inhibits collagen-induced arthritis by modulating T cell migration without affecting anti-collagen T cell responses.
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.
Yang
Yi-Fu
YF
Department of Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
Mukai
Takao
T
Gao
Ping
P
Yamaguchi
Nobuya
N
Ono
Shiro
S
Iwaki
Hiroshi
H
Obika
Satoshi
S
Imanishi
Takeshi
T
Tsujimura
Takahiro
T
Hamaoka
Toshiyuki
T
Fujiwara
Hiromi
H
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
D000577:Amides; D065100:CCR5 Receptor Antagonists; D000644:Quaternary Ammonium Compounds; D018664:Interleukin-12; D003094:Collagen; C119369:TAK 779