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* First Department of Internal Medicine and
pharmazentrum Frankfurt, and
Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit-ZAFES, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
Following the present concepts, the synthetic sphingosine analog of myriocin FTY720 alters migration and homing of lymphocytes via sphingosine 1-phosphate receptors. However, several studies indicate that the immunosuppressive properties of FTY720 may alternatively be due to tolerogenic activities via modulation of dendritic cell differentiation or based on direct effects on CD4+CD25+ regulatory T cells (Treg). As Treg play an important role for the cure of inflammatory colitis, we used the Th1-mediated 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis model to address the therapeutic potential of FTY720 in vivo. A rectal enema of TNBS was given to BALB/c mice. FTY720 was administered i.p. from days 0 to 3 or 3 to 5. FTY720 substantially reduced all clinical, histopathologic, macroscopic, and microscopic parameters of colitis analyzed. The therapeutic effects of FTY720 were associated with a down-regulation of IL-12p70 and subsequent Th1 cytokines. Importantly, FTY720 treatment resulted in a prominent up-regulation of FoxP3, IL-10, TGF
, and CTLA4. Supporting the hypothesis that FTY720 directly affects functional activity of CD4+CD25+ Treg, we measured a significant increase of CD25 and FoxP3 expression in isolated lamina propria CD4+ T cells of FTY720-treated mice. The impact of FTY720 on Treg induction was further confirmed by concomitant in vivo blockade of CTLA4 or IL-10R which significantly abrogated its therapeutic activity. In conclusion, our data provide clear evidence that in addition to its well-established effects on migration FTY720 leads to a specific down-regulation of proinflammatory signals while simultaneously inducing functional activity of CD4+CD25+ Treg. Thus, FTY720 may offer a promising new therapeutic strategy for the treatment of IBD.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Else Kroener-Fresenius-Foundation, Bad Homburg (Germany). H.H.R. was supported by the Dr.-Hans-Schleussner-Foundation. C.D. was supported by the Deutsche Forschungsgemeinschaft (GRK 757).
2 H.H.R. and J.M.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Juergen M. Stein, First Department of Internal Medicine, ZAFES, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. E-mail address: j.stein{at}em.uni-frankfurt.de
4 Abbreviations used in this paper: S1P, sphingosine-1-phosphate; IBD, inflammatory bowel disease; Treg, regulatory T cell; DC, dendritic cell; GITR, glucocorticoid-induced TNFR-related gene; TNBS, 2,4,6-trinitrobenzene sulfonic acid; BW, body weight; MPO, myeloperoxidase; LP, lamina propria; LPMC, LP mononuclear cell.
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