Stimulator of interferon genes agonists attenuate type I diabetes progression in NOD mice

Henrique Lemos, Eslam Mohamed, Lei Huang, Phillip R. Chandler, Rong Ou, Rafal Pacholczyk, Andrew L. Mellor

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Reagents that activate the signaling adaptor stimulator of interferon genes (STING) suppress experimentally induced autoimmunity in murine models of multiple sclerosis and arthritis. In this study, we evaluated STING agonists as potential reagents to inhibit spontaneous autoimmune type I diabetes (T1D) onset in non-obese diabetic (NOD) female mice. Treatments with DNA nanoparticles (DNPs), which activate STING when cargo DNA is sensed, delayed T1D onset and reduced T1D incidence when administered before T1D onset. DNP treatment elevated indoleamine 2,3 dioxygenase (IDO) activity, which regulates T-cell immunity, in spleen, pancreatic lymph nodes and pancreas of NOD mice. Therapeutic responses to DNPs were partially reversed by inhibiting IDO and DNP treatment synergized with insulin therapy to further delay T1D onset and reduce T1D incidence. Treating pre-diabetic NOD mice with cyclic guanyl-adenyl dinucleotide (cGAMP) to activate STING directly delayed T1D onset and stimulated interferon-αβ (IFN-αβ), while treatment with cyclic diguanyl nucleotide (cdiGMP) did not delay T1D onset or induce IFN-αβ in NOD mice. DNA sequence analyses revealed that NOD mice possess a STING polymorphism that may explain differential responses to cGAMP and cdiGMP. In summary, STING agonists attenuate T1D progression and DNPs enhance therapeutic responses to insulin therapy.

Original languageEnglish (US)
Pages (from-to)353-361
Number of pages9
JournalImmunology
Volume158
Issue number4
DOIs
StatePublished - Dec 1 2019

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Keywords

  • indoleamine 2,3 dioxygenase
  • stimulator of interferon genes
  • type I diabetes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Lemos, H., Mohamed, E., Huang, L., Chandler, P. R., Ou, R., Pacholczyk, R., & Mellor, A. L. (2019). Stimulator of interferon genes agonists attenuate type I diabetes progression in NOD mice. Immunology, 158(4), 353-361. https://doi.org/10.1111/imm.13122