beta-cell apoptosis in an accelerated model of autoimmune diabetes
- Author(s)
- Augstein, P; Stephens, LA; Allison, J; Elefanty, AG; Ekberg, M; Kay, TWH; Harrison, LC;
- Details
- Publication Year 1998-08,Volume 4,Issue #8,Page 495-501
- Journal Title
- MOLECULAR MEDICINE
- Publication Type
- Journal Article
- Abstract
- Background: The non-obese diabetic (NOD) mouse is a model of human type I diabetes in which autoreactive T cells mediate destruction of pancreatic islet beta cells. Although known to be triggered by cytotoxic T cells, apoptosis has not been unequivocally localized to beta cells in spontaneously diabetic NOD mice. We created a model of accelerated beta-cell destruction mediated by T cells from spontaneously diabetic NOD mice to facilitate the direct detection of apoptosis in beta cells. Materials and Methods: NOD.scid (severe combined immunodeficiency) mice were crossed with bm1 mice transgenically expressing the costimulatory molecule B7-1 (CD80) in their beta cells, to generate B7-1 NOD.scid mice. Apoptosis in islet cells was measured as DNA strand breakage by the TdT-mediated-dUTP-nick end labeling (TUNEL) technique. Results: Adoptive transfer of splenocytes from spontaneously diabetic NOD mice into B7-1 NOD.scid mice caused diabetes in recipients within 12-16 days. Mononuclear cell infiltration and apoptosis were significantly greater in the islets of B7-1 NOD.scid mice than in nontransgenic NOD.scid mice. Dual immunolabeling for TUNEL and either B7-1 or insulin, or the T cell markers CD4 and CD8, and colocalization by confocal microscopy dearly demonstrated apoptosis in beta cells as well in a relatively larger number of infiltrating T cells. The clearance time of apoptotic beta cells was estimated to be less than 6 min. Conclusions: B7-1 transgenic beta cells undergo apoptosis during their accelerated destruction in response to NOD mouse effector T cells. Rapid clearance implies that beta cells undergoing apoptosis would be detected only rarely during more protracted disease in spontaneously diabetic NOD mice.
- Publisher
- SPRINGER VERLAG
- Keywords
- NOD MOUSE; DEATH; MICE; EXPRESSION; ONSET; FAS; MEDIATORS; ANTIGEN; B7-1
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- Refer to copyright notice on published article.
Creation Date: 1998-08-01 12:00:00