Islet cell killing mediated by natural killer cells and T-lymphocytes in diabetes-prone (DP) and diabetic BB rats has been described, but other killing mechanisms may also be involved. Histopathologic studies suggest that macrophages are the first immune cells to infiltrate islets. To determine if macrophages are the first cells mediating islet damage, macrophagemediated cytotoxicity was evaluated in BB rats of different ages. Splenic macrophages isolated from DP rats at 33,100,120, and 140 days of age showed no enhanced islet killing compared with diabetes-resistant rats. Killing at diabetes onset (121 ± 14 days) was markedly increased (43 ± 9.3%) compared with agematched diabetes-resistant controls (19 ± 8.3%, P < .001). Islet inflammation was monitored at all time points. At 120 and 140 days of age, 9 of 11 (82%) DP rats had insulitis, and cytotoxicity was increased in 6 of 11 (55%) rats, which is similar to the number of DP rats that progress to diabetes. At 100 days, 3 of 6 (50%) DP rats again showed diabetic levels of killing, even in the absence of insulitis. These data indicate that 1) islet inflammation is dissociated from clinical diabetes onset, 2) splenic macrophages may have islet-killing potential before islet inflammation, 3) macrophage-mediated islet killing is elevated in all animals immediately after diabetes onset, and 4) macrophages, in addition to natural killer cells and T-lymphocytes, are responsible for cell-mediated islet destruction and thus are candidates for the first cellular effector to result in islet killing.

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