Fujii Toshimitsu, Watanabe Mamoru
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University.
Nihon Rinsho Meneki Gakkai Kaishi. 2009 Feb;32(1):7-14. doi: 10.2177/jsci.32.7.
FTY720 is a sphingosine-1-phosphate receptor modulator, which inhibits T-cell egress from lymph nodes, thereby prevents pathogenic T cells from migrating towards disease sites. In inflammatory bowel diseases, it is thought that colitogenic memory CD4+ T cells are intermittently reactivated in regional lymphoid organs, and return to inflammatory tissues. Little is known about how FTY720 controls the migration property of memory T cells and whether FTY720 could control the trafficking of T cells without the presence of lymphoid tissues. First, we here demonstrated that FTY720 prevents the development of colitis induced by the adoptive transfer of colitogenic lamina propria effector-memory CD4+ T (T(EM)) cells into SCID mice. Next, We demonstrated that FTY720 treatment suppresses the recirculation of CD4(+) T cells in splenectomized lymphotoxin-alpha(-/-) mice that lack lymph nodes and spleen. Cell number of CD4+ T cells was markedly decreased in peripheral blood of FTY720-treated mice, but conversely increased in bone marrow. Notably, FTY720 treatment prevented the development of colitis induced by transfer of colitogenic T(EM) cells into SPX LT-a(-/-) x RAG-2(-/-) mice. Collectively, the present data indicate that FTY720 treatment may offer an additional role to direct trafficking of CD4+ T cells in BM, resulting in the prevention of memory T cell-mediated diseases including inflammatory bowel diseases.
FTY720是一种鞘氨醇-1-磷酸受体调节剂，它可抑制T细胞从淋巴结逸出，从而防止致病性T细胞向疾病部位迁移。在炎症性肠病中，人们认为致结肠炎记忆CD4+ T细胞在区域淋巴器官中会间歇性地重新激活，并返回炎症组织。关于FTY720如何控制记忆T细胞的迁移特性以及FTY720在没有淋巴组织的情况下是否能够控制T细胞的运输，目前所知甚少。首先，我们在此证明FTY720可预防因将致结肠炎固有层效应记忆CD4+ T（T(EM)）细胞过继转移至SCID小鼠而诱发的结肠炎。接下来，我们证明FTY720处理可抑制在缺乏淋巴结和脾脏的脾切除淋巴毒素-α(-/-)小鼠中CD4(+) T细胞的再循环。在接受FTY720处理的小鼠外周血中，CD4+ T细胞数量显著减少，但在骨髓中则相反增加。值得注意的是，FTY720处理可预防因将致结肠炎T(EM)细胞转移至SPX LT-a(-/-) x RAG-2(-/-)小鼠而诱发的结肠炎。总体而言，目前的数据表明FTY720处理可能在直接控制CD4+ T细胞在骨髓中的运输方面发挥额外作用，从而预防包括炎症性肠病在内的记忆T细胞介导的疾病。
