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- Title
Reversal of Experimental Autoimmune Diabetes With an sCD39/Anti-CD3 Treatment.
- Authors
Fotino, Carmen; Molano, R. Damaris; Ben Nasr, Moufida; Umland, Oliver; Fraker, Christopher A.; Ulissi, Ulisse; Balasubramanian, Hari Baskar; Lunati, Maria Elena; Usuelli, Vera; Seelam, Andy Joe; Khalefa, Salma Ayman; La Sala, Christian; Gimeno, Jennifer; Mendez, Armando J.; Ricordi, Camillo; Bayer, Allison L.; Fiorina, Paolo; Pileggi, Antonello
- Abstract
Extracellular (e)ATP, a potent proinflammatory molecule, is released by dying/damaged cells at the site of inflammation and 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 NOD mice compared with prediabetic NOD mice. CD39 and CD73 were found expressed by both α- and β-cells and by different subsets of T cells. Importantly, prediabetic NOD mice displayed increased frequencies of CD3+CD73+CD39+ cells within their pancreata, pancreatic lymph nodes, and spleens. The administration of sCD39 into prediabetic NOD mice reduced their eATP levels, abrogated the proliferation of CD4+- and CD8+-autoreactive T cells, and increased the frequency of regulatory T cells, 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 compared with 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. Article Highlights: Extracellular ATP (eATP) is released by damaged and dying cells and triggers proinflammatory signals. The current study addressed the role of eATP degradation during the onset of experimental autoimmune diabetes by testing the effect of soluble CD39 We observed an increase in the peripheral levels of eATP in NOD mice and an increased expression of CD39/CD73 in the islets and in infiltrating T cells. Soluble CD39 reduced eATP levels, abrogated the proliferation of autoreactive T cells, increased the frequency of regulatory T cells, and prevented/delayed the onset of experimental autoimmune diabetes in NOD mice.
- Subjects
REGULATORY T cells; T cells
- Publication
Diabetes, 2023, Vol 72, Issue 11, p1641
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db23-0178