Faculty Collaboration Database

Innate immune activity as a predictor of persistent insulin secretion and association with responsiveness to CTLA4-Ig treatment in recent-onset type 1 diabetes. Diabetologia 2018 Nov;61(11):2356-2370

Date

09/01/2018

Pubmed ID

30167736

Pubmed Central ID

PMC6182660

DOI

10.1007/s00125-018-4708-x

Scopus ID

2-s2.0-85052798832 (requires institutional sign-in at Scopus site)   27 Citations

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^-/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.

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).

Author List

Cabrera SM, Engle S, Kaldunski M, Jia S, Geoffrey R, Simpson P, Szabo A, Speake C, Greenbaum CJ, Type 1 Diabetes TrialNet CTLA4-Ig (Abatacept) Study Group, Chen YG, Hessner MJ

Authors

Susanne M. Cabrera MD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin
Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Aniko Szabo PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Abatacept
Adolescent
Adult
Child
Diabetes Mellitus, Type 1
Female
Flow Cytometry
Humans
Immunity, Innate
Kaplan-Meier Estimate
Leukocytes, Mononuclear
Male
Young Adult