Bollyky Lab in Press at the Journal of Clinical Investigation

Autoimmune type 1 diabetes (T1D) is characterized by the immune infiltration and destruction of pancreatic β cells. Nadine Nagy and colleagues previously reported that extracellular matrix polysaccharide hyaluronan (HA) deposits accumulate within pancreatic islets in patients with T1D with autoimmune insulitis; however, it was unclear whether these deposits are important in disease pathogenesis. In this month’s issue of the JCI, this research team used the DO11.10xRIPmOVA (DORmO) mouse modelJCI cover of T1D to demonstrate that HA deposits promote islet-destructive insulitis by impairing the differentiation of Tregs. Importantly, treatment of DORmO mice after the onset of insulitis with the HA synthase inhibitor 4-methylumbelliferone (4-MU) blocked HA deposition and prevented progression to autoim- mune diabetes. These effects were recapitulated in a second model of T1D, NOD mice, in which a single week of 4-MU markedly decreased the number of diabetic mice and provided durable improvements in blood glucose levels. In addition, Nagy and colleagues showed that 4-MU treatment reestablishes a regulatory checkpoint that prevents β cell destruction and promotes the differentiation of Tregs within pancreatic islets. In vitro induction of Tregs was like- wise diminished in the presence of HA or antibodies targeting the HA receptor CD44. These findings suggest that 4-MU, which is already used to treat biliary spasm, could potentially also be used therapeutically to prevent T1D progression. The accompanying image shows insulin staining (brown), despite robust insulitis in pancreatic islets from a 15-week-old DORmO mouse treated with 4-MU for 7 weeks.

Check out the full article here: Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

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