Growing evidence indicates that adenosine receptors could be promising therapeutic targets in autoimmune diseases. Here we studied the role of adenosine receptors in controlling the course of type 1 diabetes. Diabetes in CD-1 mice was induced by multiple-low-dose-streptozotocin (MLDS) treatment and in nonobese diabetic (NOD) mice by cyclophosphamide injection. The nonselective adenosine receptor agonist 5`-N-ethylcarboxamidoadenosine (NECA) prevented diabetes development in both MLDS-challenged mice and in cyclophosphamide-treated NOD mice. The effect of NECA was reversed by the selective A<sub>2B</sub> receptor antagonist N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6- dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide (MRS 1754). The selective A<sub>1</sub> receptor agonist 2-chloro-N<sup>6</sup>-cyclopentyladenosine (CCPA) and A<sub>3</sub> receptor agonist N<sup>6</sup>-(3-iodobenzyl)-adenosine-5`-N-methyluronamide (IB-MECA) were less efficacious in ameliorating the course of diabetes. NECA inhibited diabetes in A_2A receptor KO mice and the selective A_2A receptor agonist 2-p-(2-carboxyethyl)phenethyl-amino-5`-N-ethyl-carboxamidoadenosine (CGS21680) had no effect in normal mice, indicating a lack of role of A_2A receptors. NECA failed to prevent cytokine-induced -cell death in vitro, but NECA strongly suppressed expression of the proinflammatory cytokines TNF-, MIP-1, IL-12, and IFN- in pancreata, endotoxin, or anti-CD3-stimulated splenic cells, and T helper 1 lymphocytes, indicating that the beneficial effect of NECA was due to immunomodulation. These results demonstrate that adenosine receptor ligands are potential candidates for the treatment of type 1 diabetes.--Németh, Z. H., Bleich, D., Csóka, B., Pacher, P., Mabley, J. G., Himer, L., Vizi, E. S., Deitch, E. A., Szabó, C., Cronstein, B. N., Haskó, G. Adenosine receptor activation ameliorates type 1 diabetes.