Induction of selective cell death targeting on mature T-lymphocytes in rats by a novel immunosuppressant, FTY720.
A novel immunosuppressant, FTY720, induces a rapid and marked decrease of peripheral lymphocytes, and prolong allograft survival in rats. Its mechanism of action is mediated by apoptotic cell death. In this study, we determined the time-related changes in the numbers of total lymphocytes, and the ratios of lymphocyte subpopulations in peripheral blood and lymphomyeloid organs in rats after the single oral administration of FTY720 (10 mg/kg), comparing with the effects of cyclophosphamide (80 mg/kg, ip). Total number of peripheral lymphocytes decreased significantly 3 h after the administration of the drug, while that of polymorphonuclear cells increased. T-cells were markedly decreased in number and reached a minimum of 2.3% of the control 3 days after the treatment, while B-cells reached 19.7%. T-cells decreased in spleen and liver but there was no notable change in thymus, lymph nodes, and bone marrow. The susceptibility of the cells against the drug was variant based on the type and the source of cells in vitro. Polymorphonuclear cells were the most resistant and lymph node cells the most sensitive to FTY720 after 3 h incubation with different concentration of the drug (1, 10,100 mumol/l). When incubated with 10 mumol/l of FTY720, B-cells were significantly higher in viability than the whole T- or CD4-cells. These results demonstrated that FTY720 induces cell death selectively in mature T-lymphocytes, especially CD4-lymphocytes, in peripheral blood without the depression of bone marrow.
Enosawa
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S
Department of Experimental Surgery and Bioengineering, National Children's medical Research Center, Tokyo, Japan.
Suzuki
S
S
Kakefuda
T
T
Li
X K
XK
Amemiya
H
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016131:Lymphocyte Subsets / Q000187:drug effects; D008297:Male; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D011912:Rats, Inbred ACI; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine