Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice.
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 beta 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 beta cell autoimmunity in NOD mice. Fas-Fas ligand system might be critical for autoimmune beta cell destruction leading to IDDM.
Itoh
N
N
Department of Clinical Laboratory Science, School of Allied Health Sciences, Faculty of Medicine, Osaka University, Suita, Osaka 565, Japan. nitoh@sahs.med.osaka-u.ac.jp
Imagawa
A
A
Hanafusa
T
T
Waguri
M
M
Yamamoto
K
K
Iwahashi
H
H
Moriwaki
M
M
Nakajima
H
H
Miyagawa
J
J
Namba
M
M
Makino
S
S
Nagata
S
S
Kono
N
N
Matsuzawa
Y
Y
D019264:Adoptive Transfer; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018895:Microsatellite Repeats; D010641:Phenotype; D013601:T-Lymphocytes / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
D019014:fas Receptor