Treg gene signatures predict and measure type 1 diabetes trajectory.
JCI Insight
; 4(6)2019 03 21.
Article
em En
| MEDLINE
| ID: mdl-30730852
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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Biomarcadores
/
Linfócitos T Reguladores
/
Diabetes Mellitus Tipo 1
Tipo de estudo:
Clinical_trials
/
Observational_studies
/
Prevalence_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Adolescent
/
Adult
/
Humans
País como assunto:
America do norte
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article