Abstract
Insulin-dependent diabetes mellitus is caused by autoimmune destruction of pancreatic beta cells. Non-obese diabetic (NOD) mice spontaneously develop diabetes similar to the human disease. Cytokines produced by islet-infiltrating mononuclear cells may be directly cytotoxic and can be involved in islet destruction coordinated by CD4+ and CD8+ cells. We utilized a semiquantitative RT-PCR assay to analyze in vitro the mRNA expression of TNF-alpha and IFN-gamma cytokine genes in isolated islets (N = 100) and spleen cells (5 x 10(5) cells) from female NOD mice during the development of diabetes and from female CBA-j mice as a related control strain that does not develop diabetes. Cytokine mRNAs were measured at 2, 4, 8, 14 and 28 weeks of age from the onset of insulitis to the development of overt diabetes. An increase in IFN-gamma expression in islets was observed for females aged 28 weeks (149 +/- 29 arbitrary units (AU), P<0.05, Student t-test) with advanced destructive insulitis when compared with CBA-j mice, while TNF-alpha was expressed in both NOD and CBA-j female islets at the same level at all ages studied. In contrast, TNF-alpha in spleen was expressed at higher levels in NOD females at 14 weeks (99 +/- 8 AU, P<0.05) and 28 weeks (144 +/- 17 AU, P<0.05) of age when compared to CBA-j mice. The data suggest that IFN-gamma and TNF-alpha expression in pancreatic islets of female NOD mice is associated with beta cell destruction and overt diabetes.
Highlights
Type I diabetes mellitus is a T celldependent autoimmune disease resulting in selective destruction of ß cells of the islet of Langerhans [1]
In order to investigate the expression of TNF-a and IFN-g mRNA in the autoimmune diabetes process, multiple time point analyses were performed to identify the association between cytokine gene expression and the infiltration of immune cells during disease development
Several studies have correlated cytokine expression by islets with the development of autoimmune diabetes in Non-obese diabetic (NOD) mice and have demonstrated that islet destruction is associated with increased expression of cytokines such as TNF-a and IFN-g [13,14,15,16,17,18,19,20]
Summary
Type I diabetes mellitus is a T celldependent autoimmune disease resulting in selective destruction of ß cells of the islet of Langerhans [1]. Non-obese diabetic (NOD) mice spontaneously develop type I diabetes mellitus and serve as an animal model for human type I diabetes mellitus [2,3,4]. The occurrence of a mixed lymphocytic population in pancreatic ß-islets (insulitis) can result in progressive ß cell destruction, insulin deficiency and hyperglycemia. Cells such as macrophages and dendritic cells appear early, followed by CD4+ and CD8+ T cells [5,6,7]. The first stage of insulitis occurs when the lymphocytic infiltrate is located around the islet (peri-islet) without significant ß cell
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