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The role of cytokine balance and lipid antigen presentation in the development of diabetes was studied using immunohistochemistry of cytokines in the pancreas of nonobese diabetic mice (NOD) and BALB/c mice at various ages. In both the NOD and BALB/c mice, interleukin 10 (IL-10) was expressed in the islets. IL-10 was also present in the epithelial cells of the exocrine tissue in both strains. In the NOD mice, IL-10 disappeared from both the islets and the exocrine tissue at 16 weeks of age. At this age, IL-10 was still present in the islets and exocrine tissue of the BALB/c pancreata. IL-10 was not present in the pancreata of diabetic NOD mice. IL-6 first appeared in the pancreas at 10 weeks of age and disappeared at the age of 16 weeks in both NOD and BALB/c mice. It was present in the endothelial cells. Neither the pancreata of normal BALB/c mice nor NOD mice at 2–16 weeks of age contained tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), IL-4, or IL-12. At 8 weeks of age, a few IL-2+ cells were found in the pancreas of one of three NOD mice. CD1d was already present in both strains at 2 weeks of age but disappeared from the NOD mice at 16 weeks of age. CD1d localized to walls of tubular structures probably representing collecting tubules. These results suggest that in the NOD mice the disappearance of the TH0, TH1, and TH2 responses inhibiting IL-10 from the islets at the age of 16 weeks may trigger the final stage of the immune response leading to overt diabetes. The simultaneous disappearance of CD1d suggests that activation of immune responses against lipid antigens does not play a role in this stage of the disease.