Identification of a Serum Induced Transcriptional Signature Associated with Type 1 Diabetes in the BioBreeding Rat
- Mary Kaldunski*,
- Shuang Jia*,
- Rhonda Geoffrey*,
- Joel Basken*,
- Simon Prosser*,
- Sanjay Kansra*,
- John P. Mordes†,
- Åke Lernmark§,
- Xujing Wang¶ and
- Martin J. Hessner ()*
- *The Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics at the Medical College of Wisconsin, The Children's Research Institute of Children's Hospital of Wisconsin, and the Human and Molecular Genetics Center, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA
- †Division of Endocrinology and Metabolism, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
- §Robert H. Williams Laboratory, Department of Medicine, University of Washington, Seattle, Washington, USA
- ¶Department of Physics and the Comprehensive Diabetes Center, The University of Alabama-Birmingham, Birmingham, Alabama, USA
Objective: Inflammatory mediators associated with type 1 diabetes (T1D) are dilute and difficult to measure in the periphery, necessitating development of more sensitive and informative biomarkers for studying diabetogenic mechanisms, assessing pre-onset risk, and monitoring therapeutic interventions.
Research Design and Methods: We previously utilized a novel bioassay where human T1D sera were used to induce a disease-specific transcriptional signature in unrelated, healthy peripheral blood mononuclear cells (PBMC). Here we apply this strategy to investigate the inflammatory state associated with T1D in Biobreeding (BB) rats.
Results: Consistent with their common susceptibility, sera of both spontaneously diabetic BB DRlyp/lyp and diabetes inducible BB DR+/+ rats induced transcription of cytokines, immune receptors and signaling molecules in PBMC of healthy donor rats compared to control sera. Like the human T1D signature, the DRlyp/lyp signature, which is associated with progression to diabetes, was differentiated from that of the DR+/+ by induction of many interleukin 1 (IL-1) regulated genes. Supplementing cultures with interleukin 1 receptor antagonist (IL-1Ra) modulated the DRlyp/lyp signature (p<10−6), while administration of IL-1Ra to DRlyp/lyp rats delayed onset (p=0.007) and sera of treated animals did not induce the characteristic signature. Consistent with the presence of immuno-regulatory cells in DR+/+ rats was induction of a signature possessing negative regulators of transcription and inflammation.
Conclusions: Paralleling our human studies, serum signatures in BB rats reflect processes associated with progression to T1D. Furthermore, these studies support the potential utility of this approach to detect changes in the inflammatory state during therapeutic intervention.
- Copyright © American Diabetes Association