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International Immunology Advance Access published online on December 16, 2005
International Immunology, doi:10.1093/intimm/dxh353
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received May 25, 2005
Accepted October 14, 2005

Article

A humanized anti-human Fas antibody, R-125224, induces apoptosis in type I activated lymphocytes but not in type II cells

Junichi Nakayama 1, Yukie Ogawa 1, Yasushi Yoshigae 2, Yoshiko Onozawa 1, Akiko Yonemura 1, Motoko Saito 2, Kimihisa Ichikawa 3, Takashi Yamoto 4, Tomoaki Komai 1, Toru Tatsuta 1, and Masahiko Ohtsuki 5 *

1 Biological Research Laboratories, Sankyo Co., Ltd, Tokyo 140-8710, Japan
2 Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd, Tokyo 140-8710, Japan
3 Core Technology Research Laboratories, Sankyo Co., Ltd, Tokyo 140-8710, Japan
4 Medicinal Safety Research Laboratories, Sankyo Co., Ltd, Fukuroi 437-0065, Japan
5 Global Project Management, Sankyo Pharma Development, Sankyo Pharma Inc., 399 Thornall Street, Edison, NJ 08837, USA

* To whom correspondence should be addressed.
Masahiko Ohtsuki, E-mail: mohtsuki{at}sankyopharma.com


  Abstract

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.

Keywords: activated human lymphocytes; anti-autoimmune disease therapy; DISC; lipid rafts.
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