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The S1P receptor modulator FTY720 prevents the development of experimental colitis in mice
Yasuyuki Deguchi1, Akira Andoh, Yuki Yagi
1Department of Internal Medicine, Shiga University of Medical Science, Otsu 520-2192, Japan.
Abstract:
To evaluate the therapeutic effects of the new synthetic sphingosine-1-phosphate (S1P) receptor modulator, FTY720, we investigated how FTY720 affects the development of dextran sulfate sodium (DSS)-induced colitis and CD4+CD62L+ T cell transfer colitis. BALB/c mice were fed a chow containing 3.5% (wt/wt) DSS to induce colitis. The CD4+CD62L+ T cell transfer colitis was induced by an intraperitoneal injection of CD4+CD62L+ spleen T cells into recipient CB17 SCID mice. The FTY720 was administered by lavage at a dose of 0.3 mg/kg/day. FTY720 was effective in preventing the body weight loss in the DSS-colitis model and the CD4+CD62L+ T cell transfer model. The disease activity index, histological colitis score, and MPO activity were all significantly lower in FTY720-treated mice than in the non-treated mice. Microscopically, mucosal edema, cellular infiltration and epithelial disruption were much more moderate in the FTY720-treated mice than in the non-treated mice. In both colitis models, FTY720 prevented the infiltration of CD4+ T cells into the inflamed colonic lamina propria. In conclusion, the development of DSS-colitis and CD4+CD62L+ T cell transfer colitis were significantly attenuated by FTY720. Since FTY720 is an immunosuppressive product that does not modulate T cell functions, it could be useful in the treatment of IBD patients.
Insights
FTY720, a sphingosine-1-phosphate (S1P) receptor modulator, effectively reduced symptoms in mouse models of colitis. This immunosuppressive agent prevented weight loss and inflammation, showing promise for inflammatory bowel disease (IBD) treatment.
Area of Science:
- Immunology
- Gastroenterology
- Pharmacology
Background:
- Inflammatory bowel disease (IBD) poses a significant clinical challenge.
- Current treatments have limitations, necessitating novel therapeutic strategies.
- Sphingosine-1-phosphate (S1P) receptor modulators represent a promising class of immunomodulatory agents.
Purpose of the Study:
- To evaluate the therapeutic efficacy of FTY720, a novel synthetic S1P receptor modulator.
- To investigate the effects of FTY720 on dextran sulfate sodium (DSS)-induced colitis.
- To assess FTY720's impact on CD4+CD62L+ T cell transfer colitis model.
Main Methods:
- Induction of colitis in BALB/c mice using 3.5% DSS in chow.
- Induction of T cell transfer colitis by injecting CD4+CD62L+ spleen T cells into CB17 SCID mice.
- Administration of FTY720 via lavage at 0.3 mg/kg/day.
Main Results:
- FTY720 significantly prevented body weight loss in both DSS-induced and T cell transfer colitis models.
- Treated mice exhibited lower disease activity index, histological colitis scores, and myeloperoxidase (MPO) activity.
- FTY720 markedly reduced mucosal edema, cellular infiltration, and epithelial disruption.
- Crucially, FTY720 inhibited CD4+ T cell infiltration into the colonic lamina propria in both models.
Conclusions:
- FTY720 effectively attenuates DSS-induced colitis and CD4+CD62L+ T cell transfer colitis.
- As an immunosuppressive agent that preserves T cell function, FTY720 holds potential for treating IBD.
- FTY720 demonstrates therapeutic benefits without directly modulating T cell effector functions.
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