ABSTRACT
BACKGROUND: The goal of the present study was to determine whether cytokines in the peripheral blood of naive NOD mice correlate with the disease process and thereby would provide a marker for monitoring disease activity. METHODS: Female NOD mice (5, 10 and 14-16 weeks of age) were investigated in a cross-sectional study. In the group of 14-16-week-old mice, non-diabetic and diabetic mice were analysed as different subgroups. The Th1 cytokine (IFN-gamma) and the Th2 cytokine (IL-10) were quantified in serum by sandwich enzyme-linked immunosorbent assay (ELISA). Pancreatic mRNA for IFN-gamma and IL-10 was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) from the same animals. RESULTS: Serum levels of IFN-gamma were initially low but increased with age in NOD mice, reaching the highest levels at diabetes onset (p<0.002 compared to 10 weeks). A similar rise was noted in IFN-gamma gene expression in pancreatic lesions. In contrast, an early peak of serum IL-10 levels was observed in non-diabetic NOD mice (10 weeks) at a stage where non-destructive insulitis occurs. With increasing age a continuous loss of IL-10 until progression towards diabetes was observed. The pancreatic IL-10 mRNA expression correlated with serum IL-10 changes. As a consequence, the ratio of IFN-gamma/IL-10, reflecting the Th1/Th2 balance in the serum, was significantly increased in diabetic compared to non-diabetic NOD mice (p<0.005). CONCLUSION: These results demonstrate, for the first time, that an increased Th2 pattern in the non-diabetic stage preceding a Th1 shift is associated with the development of diabetes in naive NOD mice. Serum cytokines correlate with disease progression and pancreatic cytokine expression during prediabetes. Soluble cytokines measured in the periphery are therefore promising surrogate markers of diabetes development.
