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Indirect evidence suggests there may be early influx of p-cell-directed macrophages into the islets of NOD mice, and before the onset of T-cell insulitis. We have therefore examined immunohistochemically the pancreas of young female NOD mice with monoclonal antibody F4/80 for the presence of macrophages in intraislet, pen-islet, exocrine, and perivascular regions preceding insulitis (days 18 and 22) and during early insulitis (days 30 and 40) and compared their distribution in age matched normal Swiss mouse pancreas. In the absence of insulitis (day 18 and day 22) and during very early insulitis (day 30) macrophage-positive cells had a predominantly exocrine and perivascular distribution with reduced numbers in the peri-islet area. Intraislet macrophages usually occurred singly and were sparse. At day 40, an enhanced influx of the immune cells was observed in intra- and peri-islet locations and in parallel with increased numbers in the exocrine areas. At this age, higher numbers of macrophages were observed within the islet, distributed among the T-cell infiltrate and also scattered among the endocrine cells. During the study period, the number of macrophages in the peri-, intraislet, and exocrine regions was significantly higher among NOD mice than in the Swiss mouse group (p = 0.003, p = 0.005, and p = 0.0009, respectively). In the absence of insulitis (days 18 and 22), although the number of positive cells tended to be higher in NOD mice, this difference reached statistical significance in the peri-islet area @ = 0.004). During early insulitis (days 30 and a), the number of macrophages in the three locations was significantly higher in the NOD mouse (intraislet, p = 0.02, peri-islet, p = 0.02; exocrine, p = 0.007). In the day-40 NOD mouse pancreas, the mean number of macrophages in intra-, peri-islet, and exocrine regions was higher than in the day 40 Swiss mouse and in younger tissues from both groups. We conclude that macrophages begin to be recruited within the islets and the exocrine pancreas of the NOD mouse in increasing numbers during the initiation of T-cell insulitis. However, the small number of macrophages which emigrate to the islet before the onset of insulitis in the NOD mouse may also be important in directing the influx of p-cell-specific extraislet macrophages and T lymphocytes into the islet.