Identification of a Serum-Induced Transcriptional Signature Associated With Type 1 Diabetes in the BioBreeding Rat

Abstract

OBJECTIVEInflammatory 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.RESEARCH DESIGN AND METHODSWe 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.RESULTSConsistent 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.CONCLUSIONSParalleling 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.

Use of transcriptional signatures induced in lymphoid and myeloid cell lines as an inflammatory biomarker in Type 1 diabetes

“…Collectively, our studies of T1D in humans as well as T1D in the BioBreeding rat model indicate that transcriptional signatures reflective of active autoimmunity are induced using plasma collected prior to T1D onset (32,60). These signatures appear to be mechanistically informative and show promise as a measure during therapeutic intervention.…”

“…This approach relies on the fact that lymphocytes migrate to and from sites of injury/infection/inflammation as well as circulate through lymphoid organs and requires that a sufficient percentage of peripheral cells have transcriptionally responded in a diseasespecific manner to enable detection. The less common approach has been to use subject serum or plasma to induce gene expression in healthy, unrelated third-party PBMC (32,45,60). In this application, the cells are used as reporters that sensitively respond to disease-associated factors present in the serum/plasma.…”

Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes

“…lyp/lyp as compared to BBDR rats 18 . The longitudinal studies here reveal a much more complex, dynamic, and informative process.…”

Blood-based signatures in type 1 diabetes

“…Thus, in addition to genetic variation and the endogenous innate state, additional inflammatory signals, such as those mediated by viral infections, especially in younger individuals, may impair compensatory regulatory mechanisms and promote autoimmunity. This scenario is modelled by the BioBreeding (BB) DR rat, which, similar to siblings of type 1 diabetes probands, exhibit an underlying innate inflammatory state with temporally induced immunoregulatory processes [79, 106]. BBDR rats are not spontaneously diabetic, but autoimmune diabetes can be triggered in young animals by immunological perturbations that include viral infection (reviewed in [77]).…”

“…BBDR rats are not spontaneously diabetic, but autoimmune diabetes can be triggered in young animals by immunological perturbations that include viral infection (reviewed in [77]). Our studies show that the susceptibility of BBDR rats to virally triggered diabetes declines with age and is coincident with the temporal acquisition of an IL-10- and TGF-β-mediated immunoregulated state [77, 79, 106]. In humans, prevention of type 1 diabetes will be fostered by the accurate prediction of those who will progress to onset and the development of therapies that can reinforce the default protective regulatory response.…”