Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat.
OBJECTIVE
Inflammatory mediators associated with type 1 diabetes are dilute and difficult to measure in the periphery, necessitating development of more sensitive and informative biomarkers for studying diabetogenic mechanisms, assessing preonset risk, and monitoring therapeutic interventions.


METHODS
We previously utilized a novel bioassay in which human type 1 diabetes sera were used to induce a disease-specific transcriptional signature in unrelated, healthy peripheral blood mononuclear cells (PBMCs). Here, we apply this strategy to investigate the inflammatory state associated with type 1 diabetes 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 PBMCs of healthy donor rats compared with control sera. Like the human type 1 diabetes signature, the DRlyp/lyp signature, which is associated with progression to diabetes, was differentiated from that of the DR+/+ by induction of many interleukin (IL)-1-regulated genes. Supplementing cultures with an IL-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 immunoregulatory 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 type 1 diabetes. Furthermore, these studies support the potential utility of this approach to detect changes in the inflammatory state during therapeutic intervention.
Kaldunski
Mary
M
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 theHuman and Molecular Genetics Center, Milwaukee, Wisconsin, USA.
Jia
Shuang
S
Geoffrey
Rhonda
R
Basken
Joel
J
Prosser
Simon
S
Kansra
Sanjay
S
Mordes
John P
JP
Lernmark
Ake
A
Wang
Xujing
X
Hessner
Martin J
MJ
D000818:Animals; D000941:Antigens / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics; D007378:Interleukins / Q000097:blood / Q000235:genetics; D008297:Male; D051381:Rats; D011913:Rats, Inbred BB / Q000235:genetics; D011914:Rats, Inbred BN; D015398:Signal Transduction; D014158:Transcription, Genetic
D000941:Antigens; D006684:HLA-DR Antigens; D007375:Interleukin-1; D053583:Interleukin-1beta; D007378:Interleukins