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Stimulator of Interferon Genes Agonists attenuate type I diabetes progression in NOD mice

Lookup NU author(s): Dr Henrique De Paula Lemos, Dr Lei Huang, Dr Rong Ou, Professor Andrew Mellor

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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 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 IFN, while treatment with cyclic diguanyl nucleotide (cdiGMP) did not delay T1D onset or induce IFN 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. Accepted


Publication metadata

Author(s): Lemos H, Mohamed E, Huang L, Chandler PR, Ou R, Pacholczyk R, Mellor AL

Publication type: Article

Publication status: Published

Journal: Immunology

Year: 2019

Volume: 158

Issue: 4

Pages: 353-361

Print publication date: 15/11/2019

Online publication date: 26/09/2019

Acceptance date: 16/09/2019

ISSN (print): 0019-2805

ISSN (electronic): 1365-2567

Publisher: Wiley-Blackwell Publishing Ltd.

URL: https://doi.org/10.1111/imm.13122

DOI: 10.1111/imm.13122

PubMed id: 31557322


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