Macrophage clearance defects prior to the onset of diabetes in NOD mice

An increased incidence of apoptotic p-cells in young nonobese diabetic (NOD) mice may result from decreased clearance of the dying cells from the pancreas. To investigate macrophage phagocytic ability in vivo, we examined 1) the timecourse of peritoneal macrophage phagocytosis following thioglycollate (THG)- induced peritonitis and 2) the direct injection of apoptotic thymocytes. In those experiments, macrophages from NOD mice engulfed fewer apoptotic neutrophils and thymocytes as compared to control Balblc macrophages. We also examined the production of cytokines by macrophages following apoptotic thymocyte stimulation in vivo. However, the level of transforming growth factor-pl (TGFpl) produced by peritoneal macrophages was not upregulated by apoptotic thymocytes in NOD mice. These experiments demonstrate that macrophages from NOD mice have a defect in apoptotic cell clearance and an inability to upregulate TGF-PI following apoptotic cell stimulation. These results suggest that defective macrophage function may be involved in the initiation of autoimmunity in T 1DM.