© The Rockefeller University Press, 0022-1007/1997/8/613/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 4, August 18, 1997 613-618
Requirement of Fas for the Development of Autoimmune Diabetes in Nonobese Diabetic Mice
Naoto Itoh*,
Akihisa Imagawa
,
Toshiaki Hanafusa
,
Masako Waguri
,
Koji Yamamoto
,
Hiromi Iwahashi
,
Makoto Moriwaki
,
Hiromu Nakajima
,
Junichiro Miyagawa
,
Mitsuyoshi Namba
,
Susumu Makino||,
Shigekazu Nagata
,
Norio Kono*, and
Yuji Matsuzawa
From the * Department of Clinical Laboratory Science, School of Allied Health Sciences,
Second Department of Internal Medicine, and
Department of Genetics, Faculty of Medicine, Osaka University, Suita, Osaka 565, Japan; and || Center for Experimental Animals Development, Shionogi & Co., Ltd., Koka, Shiga 520-34, Japan
Insulin-dependent diabetes mellitus (IDDM) is assumed to be a T cell–mediated autoimmune disease. To investigate the role of Fas-mediated cytotoxicity in pancreatic β cell destruction, we established nonobese diabetic (NOD)-lymphoproliferation (lpr)/lpr mice lacking Fas. Out of three genotypes, female NOD-+/+ and NOD-+/lpr developed spontaneous diabetes by the age of 10 mo with the incidence of 68 and 62%, respectively. In contrast, NOD-lpr/lpr did not develop diabetes or insulitis. To further explore the role of Fas, adoptive transfer experiments were performed. When splenocytes were transferred from diabetic NOD, male NOD-+/+ and NOD-+/lpr developed diabetes with the incidence of 89 and 83%, respectively, whereas NOD-lpr/lpr did not show glycosuria by 12 wk after transfer. Severe mononuclear cell infiltration was revealed in islets of NOD-+/+ and NOD-+/lpr, whereas islet morphology remained intact in NOD-lpr/lpr. These results suggest that Fas-mediated cytotoxicity is required to initiate β cell autoimmunity in NOD mice. Fas–Fas ligand system might be critical for autoimmune β cell destruction leading to IDDM.
Address correspondence to Naoto Itoh, Department of Clinical Laboratory Science, School of Allied Health Sciences, Faculty of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565, Japan. Phone: 81-6-879-2584; FAX: 81-6-879-2499; E-mail: nitoh{at}sahs.med.osaka-u.ac.jp
This study was presented in part at the 57th ADA Meeting, Boston, MA, June 21–24, 1997.

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