Therapeutic effects of a new lymphocyte homing reagent FTY720 in interleukin-10 gene-deficient mice with colitis.
BACKGROUND
FTY720 is a novel reagent that possesses potent immunosuppressive activity. The immunosuppression induced by FTY720 is mediated by completely different mechanisms from those of conventional immunosuppressants, that is, by altering the tissue distribution of lymphocytes rather than inhibiting activation. In this study, we examined the efficacy of FTY720 in the treatment of chronic colitis in an interleukin-10 gene-deficient (IL-0-/-) mouse model.


METHODS
FTY720 was administered orally for 4 weeks to IL-10-/- mice with clinical signs of colitis. The gross and histologic appearance of the colon and the numbers, phenotype, cytokine production, and apoptosis of lymphocytes were compared with those characteristics in a control group.


RESULTS
Single-dose administration of FTY720 resulted in the sequestration of circulating lymphocytes within the secondary lymphoid tissues. Four-week administration resulted in a significant reduction of the CD4+ T lymphocytes subpopulation in the colonic lamina propria and IFN-gamma production of the colonic lymphocytes, accompanied by a significant decrease in the severity of colitis.


CONCLUSIONS
Treatment of established colitis in IL-10-/- mice with FTY720 ameliorated the colitis, probably as a result of decreasing the number of lymphocytes in the colonic mucosa and an associated reduction in IFN-gamma production.
Mizushima
Tsunekazu
T
Department of Surgery (E1), Osaka University Graduate School of Medicine, Japan.
Ito
Toshinori
T
Kishi
Daisuke
D
Kai
Yasuyuki
Y
Tamagawa
Hiroshi
H
Nezu
Riichiro
R
Kiyono
Hiroshi
H
Matsuda
Hikaru
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects; D016753:Interleukin-10 / Q000172:deficiency; D008214:Lymphocytes / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives; D014018:Tissue Distribution / Q000187:drug effects
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016753:Interleukin-10; D007371:Interferon-gamma; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine