Innate immune activity as a predictor of persistent insulin secretion and association with responsiveness to CTLA4-Ig treatment in recent-onset type 1 diabetes
Year: 2018
Type: article
Abstract: The study aimed to determine whether discrete subtypes of type 1 diabetes exist, based on immunoregulatory profiles at clinical onset, as this has significant implications for disease treatment and prevention as well as the design and analysis of clinical trials. Using a plasma-based transcriptional bioassay and a gene-ontology-based scoring algorithm, we examined local participants from the Children’s Hospital of Wisconsin and conducted an ancillary analysis of TrialNet CTLA4-Ig trial (TN-09) participants. The inflammatory/regulatory balance measured during the post-onset period was highly variable. Notably, a significant inverse relationship was identified between baseline innate inflammatory activity and stimulated C-peptide AUC measured at 3, 6, 12, 18 and 24 months post onset among placebo-treated individuals ( p ≤ 0.015). Further, duration of persistent insulin secretion was negatively related to baseline inflammation ( p ≤ 0.012) and positively associated with baseline abundance of circulating activated regulatory T cells (CD4 + /CD45RA − /FOXP3 high ; p = 0.016). Based on these findings, data from participants treated with CTLA4-Ig were stratified by inflammatory activity at onset; in this way, we identified pathways and transcripts consistent with inhibition of T cell activation and enhanced immunoregulation. Variance among baseline plasma-induced signatures of TN-09 participants was further examined with weighted gene co-expression network analysis and related to clinical metrics. Four age-independent subgroups were identified that differed in terms of baseline innate inflammatory/regulatory bias, rate of C-peptide decline and response to CTLA4-Ig treatment. These data support the existence of multiple type 1 diabetes subtypes characterised by varying levels of baseline innate inflammation that are associated with the rate of C-peptide decline. Gene expression data files are publicly available through the National Center for Biotechnology Information Gene Expression Omnibus (accession number GSE102234).
Source: Diabetologia
Authors: Type 1 Diabetes TrialNet CTLA4-Ig (Abatacept) Study Group, Susanne M. Cabrera, Samuel Engle, Mary Kaldunski, Shuang Jia, Rhonda Geoffrey, Pippa Simpson, Aniko Szabo, Cate Speake, Carla J. Greenbaum, Yi-Guang Chen, Martin J. Hessner
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,490
Funders: Juvenile Diabetes Research Foundation United States of America, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Chicagoland Diabetes TrialNet Clinical Center, G2205763200, Plasma Induced Signatures as a Measure of Immunomodulation in T1D Clinical Trials, Quantitative measurement of T1D risk through molecular signature analysis, Continuation of UCSF as a Clinical Center for TrialNet, Clincal and Translational Science Award, NIDDK Type 1 Diabetes TrialNet Data Coordinating Center, G7485830151, Data Coordinating Center for Type 1 Diabetes TrialNet (UC4)USF: TrialNet UC4-3, Diabetes Research Center, Mechanistic and therapeutic role of the CD137-CD137L axis in Type 1 Diabetes
OpenAlex ID: W2889188387