Innate immune activity as a predictor of persistent insulin secretion and association with responsiveness to CTLA4-Ig treatment in recent-onset type 1 diabetes.

ABSTRACT: AIMS/HYPOTHESIS: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. METHODS: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. RESULTS: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-/FOXP3high; 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. CONCLUSIONS/INTERPRETATION: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. DATA AVAILABILITY:Gene expression data files are publicly available through the National Center for Biotechnology Information Gene Expression Omnibus (accession number GSE102234).

SUBMITTER: Cabrera SM 

PROVIDER: S-EPMC6182660 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature