Reversal of experimental autoimmune diabetes with a sCD39/anti-CD3 treatment

Extracellular (e)ATP, a potent pro-inflammatory molecule, is released by dying/damaged cells at the site of inflammation and it is degraded by the membrane ectonucleotidases CD39 and CD73. In this study, we sought to unveil the role of eATP degradation in autoimmune diabetes, we then assessed the effect of soluble CD39 (sCD39) administration in prevention and reversal studies in NOD mice as well as in mechanistic studies. Our data showed that eATP levels were increased in hyperglycemic NODs as compared to pre-diabetic NODs. CD39 and CD73 were found expressed by both α- and β-cells and by different subsets of T-cells. Importantly, pre-diabetic NOD mice displayed increased frequencies of CD3⁺CD73⁺CD39⁺ cells within their pancreata, pLNs and spleens. The administration of sCD39 into pre-diabetic NODs reduced their eATP levels, abrogated the proliferation of CD4⁺- and CD8⁺-autoreactive T-cells and increased the frequency of Tregs; while delaying the onset of T1D. Notably, concomitant administration of sCD39 and anti-CD3 showed a strong synergism in restoring normoglycemia in newly hyperglycemic NOD mice as compared to monotherapy with anti-CD3 or with sCD39. The eATP/CD39 pathway plays an important role in the onset of T1D and its targeting might represent a potential therapeutic strategy in T1D.