Therapeutic effect of a new immunosuppressive agent, everolimus, on interleukin-10 gene-deficient mice with colitis.
A limited number of therapeutic strategies are currently available for patients with inflammatory bowel disease (IBD). In particular, the maintenance therapy after remission in Crohn's disease (CD) is not satisfactory and new approaches are needed. Interleukin-10 gene-deficient (IL-10-/-) mice, a well-characterized experimental model of CD, develop severe chronic colitis due to an aberrant Th1 immune response. Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), a new immunosuppressive reagent, has been used successfully in animal models for heart, liver, lung and kidney transplantation. In the present study, we examined the efficacy of everolimus in the treatment of chronic colitis in an IL-10-/- mouse model. Everolimus was administered orally for a period of 4 weeks to IL-10-/- mice with clinical signs of colitis. The gross and histological appearances of the colon and the numbers, phenotype and cytokine production of lymphocytes were compared with these characteristics in a control group. The 4-week administration of everolimus resulted in a significant decrease in the severity of colitis, together with a significant reduction in the number of CD4+ T cells in the colonic lamina propria as well as IFN-gamma production in colonic lymphocytes. Everolimus treatment of established colitis in IL-10-/- mice ameliorated the colitis, probably as a result of decreasing the number of CD4+ T cells in the colonic mucosa and an associated reduction in IFN-gamma production.
Matsuda
C
C
Department of Surgery (E1), Osaka University Graduate School of Medicine, Japan.
Ito
T
T
Song
J
J
Mizushima
T
T
Tamagawa
H
H
Kai
Y
Y
Hamanaka
Y
Y
Inoue
M
M
Nishida
T
T
Matsuda
H
H
Sawa
Y
Y
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002478:Cells, Cultured; D003424:Crohn Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D000068338:Everolimus; D005260:Female; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000172:deficiency*; D007413:Intestinal Mucosa / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016896:Treatment Outcome
D016207:Cytokines; D007166:Immunosuppressive Agents; D016753:Interleukin-10; D007371:Interferon-gamma; D000068338:Everolimus; D020123:Sirolimus