PANCREATIC EXPRESSION OF INTERLEUKIN-4 ABROGATES INSULITIS AND AUTOIMMUNE DIABETES IN NONOBESE DIABETIC (NOD) MICE

Diabetes in nonobese diabetic (NOD) mice is a T cell-dependent autoimm une disease. The destructive activities of autoreactive T cells have b een shown to be tightly regulated by effector molecules. In particular , T helper (Th) 1 cytokines have been linked to diabetes pathogenesis, whereas Th2 cytokines and the cells that release them have been postu lated to be protective from disease. To test this hypothesis, we gener ated transgenic NOD mice that express interleukin (IL) 4 in their panc reatic beta cells under the control of the human insulin promoter. We found that transgenic NOD-IL-4 mice, both females and males, were comp letely protected from insulitis and diabetes. Induction of functional tolerance to islet antigens in these mice was indicated by their inabi lity to reject syngeneic pancreatic islets and the failure of diabetog enic spleen cells to induce diabetes in transgenic NOD-IL-4 recipients . Interestingly, however, islet expression of IL-4 was incapable of pr eventing islet rejection in overtly diabetic NOD recipient mice. These results demonstrate that the Th2 cytokine IL-4 can prevent the develo pment of autoimmunity and destructive autoreactivity in the NOD mouse. Its ability to regulate the disease process in the periphery also ind icates that autoimmune diabetes in NOD mice is not a systemic disease, and it can be modulated from the islet compartment.