Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice

N Itoh, A Imagawa, T Hanafusa, M Waguri… - The Journal of …, 1997 - rupress.org
N Itoh, A Imagawa, T Hanafusa, M Waguri, K Yamamoto, H Iwahashi, M Moriwaki…
The Journal of experimental medicine, 1997rupress.org
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 …
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.
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