Author:
Marro Brett S.,Ware Brian C.,Zak Jaroslav,de la Torre Juan Carlos,Rosen Hugh,Oldstone Michael B. A.
Abstract
Blockade of IFN-α but not IFN-β signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouse Rip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune “antiself” T cells to the external boundaries around the islets and prevented their entry into the islets so they could not be positioned to engage, kill, and thus remove insulin-producing β cells. Second, CYM-5442 induced an exhaustion signature in antiself T cells by up-regulating the negative immune regulator receptor genes Pdcd1, Lag3, Ctla4, Tigit, and Btla, thereby limiting their killing ability. By such means, insulin production was preserved and glucose regulation maintained, and a mechanism for S1PR1 immunomodulation described.
Funder
HHS | National Institutes of Health
Publisher
Proceedings of the National Academy of Sciences
Cited by
44 articles.
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