T1207 FTY720 Suppresses the Development of Colitis in Lymphoid-Null Mice By Trapping Colitogenic CD4 + T Cells in Bone Marrow

Abstract

Backgroud & Aims: A sphingosine-1-phosphate receptor modulator, FTY720, suppresses T-cell egress from lymph nodes, and therefore prevents T cells to migrate to sites of inflammation, resulting in the effectiveness in inhibiting autoimmunity in various animal models. However, little is known whether FTY720 controls the trafficking of CD4+ T cells without an impact of lymphoid tissues, such as lymph nodes and spleen. Methods: We here ask if FTY720 treatment suppresses the recirculation of CD4+ T cells and the development of colitis in colitogenic CD4+ memory T cell-transferred splenectomized (SPX) lymphotoxinα-/(LT-α-/-) mice that lack lymph nodes, Peyer's patches, and spleen. Results: In a shortterm transfer experiment, the recovered cell number of adoptively transferred Ly5.1+CD4+ T cells to FTY720-treated SPX LT-α-/mice (Ly5.2+) was markedly decreased in the blood, but conversely increased in the bone marrow (BM). Furthermore, FTY720 treatment prevented the development of colitis induced by adoptive transfer of colitogenic lamina propria (LP) CD4+ CD44highCD62Leffector-memory T (TEM) cells obtained from colitic CD4+CD45RBhigh T cell-transferred mice into new SPX LT-α-/x RAG-2-/mice, and suppressed IFN-γ and TNF-α production by LP CD4+ T cells. In addition, the number of peripheral blood and LP CD4+ T cells in the FTY720-treated SPX LT-α-/x RAG-2-/recipients was significantly reduced as compared with the untreated control mice. Conclusions: Collectively, the present data indicate that FTY720 treatment may offer the additional role not only to control trafficking of CD4+ T cells in the BM but also to directly modulate the memory T cell-mediated diseases including inflammatory bowel diseases. (FTY720 from Novaltis)