A mechanism has been identified that amplifies the autoimmune reaction in an early stage of pancreatic islet autoimmunity before it progresses to type 1 diabetes.
The German researchers say their findings, which are published in the latest edition of Science Translational Medicine, put them in a position to begin preclinical tests in humanised models to see if they can develop ways for the immune system to stop working against its own islet cells.
Dr Carolin Daniel, of Helmholtz Zentrum München, and her team looked at why Tregs fail to protect the islet cells in type 1 diabetes.
They found that miRNA181a and NFAT5 molecules cause fewer Tregs to be produced during islet autoimmunity onset and that enables the immune system to get out of control and attack.
“We showed that miRNA181a leads to the activation of the transcription factor NFAT5 during islet autoimmunity onset,” she said.
“The consequence is an inhibition of Treg induction and thus increased immune activation.”
While investigating a preclinical model with early-stage islet autoimmunity, they found that if they interrupted the miRNA181a/NFAT5-axis, there was a significantly lower activation of the immune system and an increased formation of Tregs. This was achieved both by the pharmacological inhibition of miRNA181a as well as of NFAT5.
Professor Anette-Gabriele Ziegler, director of the Institute of Diabetes Research (IDF), said: “The targeted inhibition of miRNA181a or NFAT5 could open up new approaches to reduce the activity of the immune system against its own islet cells.
“The combination with other immune modulating therapeutic approaches would also be conceivable as an intervention.”
Humanised models will be used to establish if the combination of insulin vaccination and inhibition of the miRNA181a/NFAT5 axis leads to a more tolerant immune system towards insulin-producing cells.
Serr, I. et al. A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune Type 1 diabetes. Science Translational Medicine 3 January 2018; doi: 10.1126/scitranslmed.aag1782 [abstract]
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