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Treg gene signatures predict and measure type 1 diabetes trajectory
Anne M. Pesenacker, … , Scott J. Tebbutt, Megan K. Levings
Anne M. Pesenacker, … , Scott J. Tebbutt, Megan K. Levings
Published February 7, 2019
Citation Information: JCI Insight. 2019;4(6):e123879. https://doi.org/10.1172/jci.insight.123879.
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Clinical Medicine Endocrinology Immunology

Treg gene signatures predict and measure type 1 diabetes trajectory

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Abstract

BACKGROUND. Multiple therapeutic strategies to restore immune regulation and slow type 1 diabetes (T1D) progression are in development and testing. A major challenge has been defining biomarkers to prospectively identify subjects likely to benefit from immunotherapy and/or measure intervention effects. We previously found that, compared with healthy controls, Tregs from children with new-onset T1D have an altered Treg gene signature (TGS), suggesting that this could be an immunoregulatory biomarker. METHODS. nanoString was used to assess the TGS in sorted Tregs (CD4+CD25hiCD127lo) or peripheral blood mononuclear cells (PBMCs) from individuals with T1D or type 2 diabetes, healthy controls, or T1D recipients of immunotherapy. Biomarker discovery pipelines were developed and applied to various sample group comparisons. RESULTS. Compared with controls, the TGS in isolated Tregs or PBMCs was altered in adult new-onset and cross-sectional T1D cohorts, with sensitivity or specificity of biomarkers increased by including T1D-associated SNPs in algorithms. The TGS was distinct in T1D versus type 2 diabetes, indicating disease-specific alterations. TGS measurement at the time of T1D onset revealed an algorithm that accurately predicted future rapid versus slow C-peptide decline, as determined by longitudinal analysis of placebo arms of START and T1DAL trials. The same algorithm stratified participants in a phase I/II clinical trial of ustekinumab (αIL-12/23p40) for future rapid versus slow C-peptide decline. CONCLUSION. These data suggest that biomarkers based on measuring TGSs could be a new approach to stratify patients and monitor autoimmune activity in T1D. FUNDING. JDRF (1-PNF-2015-113-Q-R, 2-PAR-2015-123-Q-R, 3-SRA-2016-209-Q-R, 3-PDF-2014-217-A-N), the JDRF Canadian Clinical Trials Network, the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (UM1AI109565 and FY15ITN168), and BCCHRI.

Authors

Anne M. Pesenacker, Virginia Chen, Jana Gillies, Cate Speake, Ashish K. Marwaha, Annika Sun, Samuel Chow, Rusung Tan, Thomas Elliott, Jan P. Dutz, Scott J. Tebbutt, Megan K. Levings

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Figure 6

Altered Treg gene signature in T2D compared with T1D and healthy controls.

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Altered Treg gene signature in T2D compared with T1D and healthy control...
The Treg gene signature was measured in sorted CD25hiCD127lo Tregs and PBMCs from the indicated age- and sex-matched cohorts using the nCounter SPRINT system. For Tregs: T2D, n = 29; T1D, n = 7; and healthy controls (HC), n = 9. For PBMCs: T2D, n = 33; T1D, n = 10; and HCs, n = 9. Shown is a principal component analysis representing expression of all 37 genes by sample group in (A) Tregs or (B) PBMCs. 95% confidence intervals are overlaid as ellipses. T1D, type 1 diabetes; T2D, type 2 diabetes.

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