FTY720 suppresses the development of colitis in lymphoid-null mice by modulating the trafficking of colitogenic CD4+ T cells in bone marrow.
2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720) suppresses T-cell egress from LN, thereby preventing pathogenic T cells from migrating toward disease sites. However, little is known about whether FTY720 could control the trafficking of T cells without the presence of lymphoid tissues. Here we demonstrate that FTY720 treatment suppresses the recirculation of CD4(+) T cells in splenectomized (SPX) lymphotoxin-alpha(-/-) (LT-alpha(-/-)) mice that lack LN and spleen, as shown by peripheral blood (PB) lymphopenia in FTY720-treated SPX LT-alpha(-/-) mice. In a short-term transfer experiment, the cell number of transferred Ly5.1(+)CD4(+) T cells recovered from host FTY720-treated SPX LT-alpha(-/-) mice (Ly5.2(+)) was markedly decreased in PB, but conversely increased in BM. Notably, FTY720 treatment prevented the development of colitis that is otherwise induced in untreated SPX LT-alpha(-/-) x RAG-2(-/-) mice upon transfer of colitic lamina propria CD4(+) T cells. In such mice, the number of CD4(+) T cells in PB or lamina propria of FTY720-treated SPX LT-alpha(-/-) x RAG-2(-/-) recipients was significantly reduced, but that in the BM was significantly increased as compared with untreated control mice. Altogether, the present results indicate that FTY720 treatment may offer an additional role to direct trafficking of CD4(+) T cells in BM, resulting in the prevention of colitis.
Fujii
Toshimitsu
T
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Tomita
Takayuki
T
Kanai
Takanori
T
Nemoto
Yasuhiro
Y
Totsuka
Teruji
T
Sakamoto
Naoya
N
Nakamura
Tetsuya
T
Tsuchiya
Kiichiro
K
Okamoto
Ryuichi
R
Watanabe
Mamoru
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D000068876:Fingolimod Hydrochloride; D008197:Lymph Node Excision; D008221:Lymphoid Tissue / Q000276:immunology* / Q000601:surgery; D008233:Lymphotoxin-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013156:Splenectomy
D016207:Cytokines; D008233:Lymphotoxin-alpha; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine