Evidence that FTY720 induces T cell apoptosis in vivo.
The immunosuppressant FTY720 induces a drastic decrease in blood lymphocytes, especially T cells; a decrease which is assumed to be the immunosuppressive mechanism of this drug. FTY720 causes cell death in vitro in lymphocytes and leukemia cells. However, the deletion mechanism of blood lymphocytes in vivo remains unclear. We investigated whether administration of FTY720 induced lymphocyte apoptosis in blood circulation. A marked decrease in the number of blood lymphocytes was observed within an hour after a single oral administration of FTY720 at doses of 5-10 mg/kg in rats and mice. Experiments using fluorescein isothiocyanate (FITC)-Annexin V and APO-BRDU methods revealed that FTY720 induced blood lymphocyte apoptosis in a dose-dependent manner. On the other hand, lymphocyte homing to Peyer's patches was proposed as the mechanism underlying the blood lymphocyte decrease at these doses. However, similar results were obtained when using aly/aly mice, which lack Peyer's patches and lymph nodes. Thus, we concluded that apoptosis of blood lymphocytes was induced immediately after administration of FTY720, and the cells could be immediately scavenged by phagocytes or the reticuloendothelial system in addition to Peyer's patches homing. We also concluded that T cells were highly sensitive to FTY720, which induced apoptosis in vivo.
Nagahara
Y
Y
Division of Research Promotion, National Children's Medical Research Center, 3-35-31 Taishido, Setagaya-ku, Tokyo 154-8509, Japan.
Enosawa
S
S
Ikekita
M
M
Suzuki
S
S
Shinomiya
T
T
D000284:Administration, Oral; D000818:Animals; D017304:Annexin A5; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D000068876:Fingolimod Hydrochloride; D016650:Fluorescein-5-isothiocyanate; D006098:Granulocytes / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*
D017304:Annexin A5; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D016650:Fluorescein-5-isothiocyanate; D013110:Sphingosine