DISEASE-PROTECTED MAJOR HISTOCOMPATIBILITY COMPLEX EA-TRANSGENIC NONOBESE DIABETIC (NOD) MICE SHOW INTERLEUKIN-4 PRODUCTION NOT SEEN IN SUSCEPTIBLE EA-TRANSGENIC AND NONTRANSGENIC NOD MICE

The non-obese diabetic (NOD) mouse is an animal model for insulin-depe ndent diabetes that has many similarities to the human disease. NOD mi ce transgenic for the Ea gene, allowing expression of the E molecule, are protected from diabetes and rarely develop insulitis. An Ea transg ene mutated in the promoter region, (Delta Y) lacks E expression on mo st B cells, thymic medullary epithelium and primary antigen-presenting cells, and confers no protection whatsoever. We have used these trans genic NOD mice, together with non-transgenic NOD mice, to study the co rrelation of E expression and production of interleukin-4 (IL-4) and i nterferon-gamma (IFN-gamma). We show that protected E-transgenic NOD m ice have elevated levels of IL-4 compared with non-transgenic mice, bo th in the thymus and in the periphery. However, susceptible Delta Y-tr ansgenic mice have elevated thymic IL-4 levels, but express almost as little IL-4 as non-transgenic NOD mice in the periphery. This drop in peripheral IL-4 production seen in Delta Y-transgenic: mice thus corre lates with the decreased E expression in the periphery of Delta Y-tran sgenic NOD mice. In contrast, there were no differences in IFN-gamma p roduction between the three NOD lines. We suggest that Ea-transgenic N OD mice have E-selected regulatory T cells producing IL-4, which are s ubsequently activated by E-expressing primary antigen-presenting cells in the periphery. This activation would then be instrumental for the E-mediated protection from disease in NOD mice. Such a process would e xplain the total absence of protection in Delta Y-transgenic NOD mice, despite their widespread E expression.