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Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjogren Syndrome-like Inflammation.

ABSTRACT: Human genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27R?. In contrast to wild-type NOD mice, both NOD.Il27^-/- and NOD.Il27ra^-/- strains are completely resistant to T1D. IL-27 from myeloid cells and IL-27 signaling in T cells are critical for T1D development. IL-27 directly alters the balance of regulatory T cells (Tregs) and T helper 1 (Th1) cells in pancreatic islets, which in turn modulates the diabetogenic activity of CD8 T cells. IL-27 also directly enhances the effector function of CD8 T cells within pancreatic islets. In addition to T1D, IL-27 signaling in T cells is also required for lacrimal and salivary gland inflammation in NOD mice. Our study reveals that IL-27 contributes to autoimmunity in NOD mice through multiple mechanisms and provides substantial evidence to support its pathogenic role in human T1D.

SUBMITTER: Ciecko AE

PROVIDER: S-EPMC6914223 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjögren Syndrome-like Inflammation.

Ciecko Ashley E AE Foda Bardees B Barr Jennifer Y JY Ramanathan Sheela S Atkinson Mark A MA Serreze David V DV Geurts Aron M AM Lieberman Scott M SM Chen Yi-Guang YG

Cell reports 20191201 10

Human genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27Rα. In contrast to wild-type NOD mice, both NOD.Il27<sup>-/-</sup> and NOD.Il27ra<sup>-/-</sup> strains are completely resistant to T1D. IL-27 from myeloid cells and IL-27 signaling in T cells are critical for T1D development. I ...[more]

PMID: 31801074

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Project description:ImportancePrimary Sjögren syndrome (pSS) is a systemic autoimmune disease associated with dysregulated immune cells, with no efficient therapy. There is a need to study potential therapeutic approaches.ObjectiveTo investigate the efficacy, safety, and immune response of low-dose interleukin 2 (LD-IL-2) in the treatment of pSS.Design, setting, and participantsA double-blind, placebo-controlled randomized clinical trial was conducted with a 2-group superiority design from June 2015 to August 2017. Sixty patients, aged 18 to 70 years, were recruited from Peking University People's Hospital. Efficacy analyses were based on the intention-to-treat (ITT) principle. Data were analyzed from December 2018 to March 2020.InterventionsPatients with pSS were treated with LD-IL-2 or placebo for 12 weeks and accompanied by 12 weeks of follow-up.Main outcomes and measuresThe primary end point was defined as a 3-point or greater improvement on the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) by week 24. The secondary end points included other clinical responses, safety, and changes of immune cell subsets at week 12 and 24.ResultsSixty patients with pSS were recruited, with 30 in the LD-IL-2 group (mean [SD] age, 47.6 [12.8] years; 30 [100%] women) and 30 in the placebo group (mean [SD] age, 51.0 [11.9] years; 30 [100%] women), and 57 completed the trial. More patients in the LD-IL-2 group (20 [66.7%]) achieved ESSDAI score reduction of at least 3 points than in the placebo group (8 [26.7%]) at week 24 (P = .004). There were greater resolutions of dryness, pain, and fatigue in the LD-IL-2 group than placebo group at week 12 (dryness: difference, -18.33 points; 95% CI, -28.46 to -8.21 points; P = .001; pain: difference, -10.33 points; 95% CI, -19.38 to -1.29 points; P = .03; fatigue: difference, -11.67 points; 95% CI, -20.65 to -2.68 points; P = .01). No severe adverse events were observed in either group. In addition, the LD-IL-2 group showed a significant decrease in infection compared with the placebo group (1 [3.3%] vs 9 [30.0%]; P = .006). Immunological analysis revealed that LD-IL-2 promoted an expansion of regulatory T cells and regulatory CD24highCD27+ B cells.Conclusions and relevanceIn this randomized clinical trial, LD-IL-2 was effective and well tolerated in patients with pSS, and it restored immune balance, with enhanced regulatory T cells and CD24highCD27+ B cells.Trial registrationClinicalTrials.gov Identifier: NCT02464319.

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Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjogren Syndrome-like Inflammation.

Publications

Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjögren Syndrome-like Inflammation.

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