Adenosine receptor activation ameliorates type 1 diabetes

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(2B) receptor antagonist N-( 4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide ( MRS 1754). The selective A(1) receptor agonist 2-chloro-N-6-cyclopentyladenosine ( CCPA) and A(3) receptor agonist N-6-( 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 A2A 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 A2A receptors. NECA failed to prevent cytokine-induced beta-cell death in vitro, but NECA strongly suppressed expression of the proinflammatory cytokines TNF-alpha, MIP-1 alpha, IL-12, and IFN-gamma 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.