Lack of the mediators of innate immunity attenuate the development of autoimmune diabetes in mice.

Interleukin 15 (IL-15) and Interleukin 18 (IL-18) are key cytokines produced by macrophages during innate immune response. These cytokines can profoundly affect subsequent adaptive immune responses including autoimmunity. We have investigated the role of IL-15 and IL-18 in the development of autoimmune diabetes in mice induced by multiple low dose streptozotocin (MLD-STZ). To analyze the role of IL-15, we tested the effects of a soluble murine IL-15 receptor alpha-chain (smIL-15Ralpha), on the development of MLD-STZ in C57BL/6 mice. Animals were treated with 10 daily injections of 32 microg of smIL-15Ralpha starting on the first day of diabetes induction. This treatment significantly attenuated the development of diabetes as evaluated by significantly lower glycemia compared with control mice treated with an inactive mutant form of sIL-15Ra. To directly address the role of IL-18 in MLD-STZ we used IL-18 knockout (KO) mice on DBA/1 background. IL-18 deficient mice were significantly more resistant to the induction of diabetes compared with the wild-type controls and did not develop the typical mononuclear cell infiltrates in the islets. Taken together our data suggest that the innate mediators, IL-15 and IL-18, are essential for the development of diabetes and may be important targets in prevention and early treatment of autoimmune diabetes.