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 β cells. Although known to be triggered by cytotoxic T cells, apoptosis has not been unequivocally localized to β cells in spontaneously diabetic NOD mice. We created a model of accelerated β-cell destruction mediated by T cells from spontaneously diabetic NOD mice to facilitate the direct detection of apoptosis in β 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 β 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 clearly demonstrated apoptosis in β cells as well in a relatively larger number of infiltrating T cells. The clearance time of apoptotic β cells was estimated to be less than 6 min. Conclusions: B7-1 transgenic β cells undergo apoptosis during their accelerated destruction in response to NOD mouse effector T cells. Rapid clearance implies that β cells undergoing apoptosis would be detected only rarely during more protracted disease in spontaneously diabetic NOD mice.
|Number of pages||7|
|Publication status||Published - 27 Oct 1998|