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JCI Insight. 2019 Mar 21;4(6). pii: 123879. doi: 10.1172/jci.insight.123879. eCollection 2019 Mar 21.

Treg gene signatures predict and measure type 1 diabetes trajectory.

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Department of Surgery, University of British Columbia (UBC), and BC Children's Hospital Research Institute (BCCHRI), Vancouver, British Columbia, Canada.
Department of Medicine and Centre for Heart Lung Innovation, UBC, and Prevention of Organ Failure (PROOF) Centre of Excellence, St. Paul's Hospital, Vancouver, British Columbia, Canada.
Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, Washington, USA.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Department of Dermatology, UBC, and BCCHRI, Vancouver, British Columbia, Canada.
Department of Pathology, Sidra Medicine, Weill Cornell Medicine, Doha, Qatar.
Department of Medicine, UBC, and BCDiabetes, Vancouver, British Columbia, Canada.



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.


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.


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 (╬▒IL-12/23p40) for future rapid versus slow C-peptide decline.


These data suggest that biomarkers based on measuring TGSs could be a new approach to stratify patients and monitor autoimmune activity in T1D.


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.


Bioinformatics; Diabetes; Endocrinology; Immunology; Tolerance

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