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.
Keywords:
IFN-alpha; S1PR1; type 1 diabetes; type I interferon.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Diabetes Mellitus, Type 1 / immunology
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Diabetes Mellitus, Type 1 / prevention & control*
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Disease Models, Animal
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Disease Progression
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Indans / administration & dosage*
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Indans / pharmacology
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Insulin / metabolism
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Insulin-Secreting Cells / immunology
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Interferon-alpha / metabolism*
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Islets of Langerhans / immunology
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Mice
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Oxadiazoles / administration & dosage*
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Oxadiazoles / pharmacology
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Prediabetic State / drug therapy*
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Prediabetic State / immunology
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Receptors, Immunologic / metabolism
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Receptors, Lysosphingolipid / agonists*
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Signal Transduction / drug effects
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Sphingosine-1-Phosphate Receptors
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T-Lymphocytes / drug effects*
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T-Lymphocytes / immunology
Substances
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2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino)ethanol
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Indans
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Insulin
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Interferon-alpha
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Oxadiazoles
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Receptors, Immunologic
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Receptors, Lysosphingolipid
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S1pr1 protein, mouse
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Sphingosine-1-Phosphate Receptors