A humanized anti-human Fas antibody, R-125224, induces apoptosis in type I activated lymphocytes but not in type II cells.
Fas-mediated apoptosis plays an important role in the immune system, including the elimination of autoreactive lymphoid cells. The Fas-mediated signaling pathway is classified into two types, type I and type II, in human lymphoid cell lines. We investigated whether a humanized anti-human Fas mAb, R-125224, has cell selectivity in induction of apoptosis. R-125224 induced apoptosis in H9 cells, SKW6.4 cells and activated human lymphocytes when cross-linked with anti-human IgG. On the other hand, R-125224 did not induce apoptosis in HPB-ALL cells, Jurkat cells or human hepatocytes. By analysis of death-inducing signaling complex formation, it was demonstrated that R-125224 induced apoptosis selectively in type I cells but not in type II cells. Type I cells also expressed more Fas and had more Fas-clustering activity than type II cells. Moreover, co-localization of these clusters and GM1, which is an sphingoglycolipid associated with lipid rafts, was detected. It was also shown that R-125224 treatment could reduce the number of activated human CD3+Fas+ cells in a SCID mouse model in vivo. Thus, we demonstrated that R-125224 induces apoptosis specifically in type I cells in vitro and in vivo.
Nakayama
Junichi
J
Biological Research Laboratories, Sankyo Co., Ltd, Tokyo 140-8710, Japan.
Ogawa
Yukie
Y
Yoshigae
Yasushi
Y
Onozawa
Yoshiko
Y
Yonemura
Akiko
A
Saito
Motoko
M
Ichikawa
Kimihisa
K
Yamoto
Takashi
T
Komai
Tomoaki
T
Tatsuta
Toru
T
Ohtsuki
Masahiko
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology; D006801:Humans; D007152:Immunologic Capping / Q000187:drug effects / Q000276:immunology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D019014:fas Receptor