In vivo analysis of Fas antigen-mediated apoptosis: effects of agonistic anti-mouse Fas mAb on thymus, spleen and liver.
Fas antigen (Fas/CD95) is a cell surface receptor protein that mediates apoptosis-inducing signals. To analyze the function of Fas in vivo, we examined the effects of agonistic anti-Fas antibodies in mice. The i.p. administration of the hamster anti-mouse Fas mAb, RK-8, which induced apoptosis both in vivo and in vitro, did not kill adult mice, whereas those given the another hamster anti-mouse Fas mAb, Jo2, rapidly died of fulminant hepatitis with hemorrhage. Histological analyses of mice given RK-8 indicated severe damage of the thymus, and moderate damage of the spleen and liver. Most of the thymocytes and some hepatocytes underwent apoptosis within 1 day of administration. Flow cytometry revealed that CD4+ T cells were more sensitive to Fas-mediated apoptosis than CD8+ T cells. At day 7 after administration, the thymus was atrophied. These in vivo effects of RK-8 were transient; the thymus was regenerated, and the liver and spleen were apparently normal 1 month after injection. The administration of RK-8 into newborn mice caused severe damage of the liver and thymus. Most of the hepatocytes died and jaundice was induced. The newborn mice died within 1 week. Most hepatocytes of newborn mice may be more sensitive to apoptosis-inducing signals through Fas than those of adult mice. These results indicated that functional Fas, which introduces the death signal in vivo, is expressed on thymocytes, CD4+ splenocytes, and some adult and most newborn mouse hepatocytes.
Nishimura
Y
Y
The Pharmaceutical Basic Research Laboratories, JT Inc., Yokohama, Japan.
Hirabayashi
Y
Y
Matsuzaki
Y
Y
Musette
P
P
Ishii
A
A
Nakauchi
H
H
Inoue
T
T
Yonehara
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D000961:Antilymphocyte Serum / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D002478:Cells, Cultured; D006224:Cricetinae; D006825:Hybridomas; D007274:Injections, Intraperitoneal; D008099:Liver / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D019014:fas Receptor