The in vivo induction of lymphocyte apoptosis in MRL-lpr/lpr mice treated with FTY720.
The in vitro treatment of lpr thymocytes with FTY720 resulted in a dose-dependent reduction in cell viability due to apoptosis. In order to study the effect of FTY720 in vivo, lpr mice received an oral daily dose of 1 mg/kg FTY720 for 14 days, beginning at 16 weeks of age which was when the animals were developing massive lymphoadenopathy. Compared with untreated lpr mice, FTY720-treated lpr mice had significantly prolonged lives. At 24 weeks of age, treated mice demonstrated markedly reduced weights of the spleen and lymph nodes, and the proportion of CD3+ B220+ and CD4- CD8- cells in the thymus, spleen and lymph nodes decreased markedly. In addition, in these mice the percentage of CD4+ CD8+ and CD3- B220- cells in the thymus and the percentage of CD4+ CD8-, CD4- CD8+, CD3+ B220- and CD3- B220+ cells in the spleen returned to almost the normal values observed in wild-type mice. Histological observation 1 day after the final administration of FTY720 revealed a remarkable infiltration of neutrophils in the lymphoid organs. Apoptotic cells were detected in all the lymphoid organs using in situ DNA nick-end labelling. Electron microscopy showed that the apoptotic cells were ingested by phagocytes. FTY720 therapy is thus highly effective in Fas-mutant animals with abnormally expanding lymphocytes.
Suzuki
S
S
Department of Experimental Surgery and Bioengineering, National Children's Medical Research Center, Tokyo, Japan.
Li
X K
XK
Shinomiya
T
T
Enosawa
S
S
Amemiya
H
H
Amari
M
M
Naoe
S
S
D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D017252:CD3 Complex / Q000032:analysis; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011409:Propylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000187:drug effects* / Q000648:ultrastructure; D013950:Thymus Gland / Q000187:drug effects; D019014:fas Receptor / Q000276:immunology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D019014:fas Receptor; D017493:Leukocyte Common Antigens; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine