Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptional Signatures as a Disease-Specific and Predictive Inflammatory Biomarker for Type 1 Diabetes [T1D_114]

ABSTRACT: The complex milieu of inflammatory mediators associated with many diseases is often too dilute to directly measure in the periphery, necessitating development of more sensitive measurements suitable for mechanistic studies, earlier diagnosis, guiding selection of therapy, and monitoring interventions. Previously, we determined that plasma of recent-onset (RO) Type 1 diabetes (T1D) patients induce a proinflammatory transcriptional signature in fresh peripheral blood mononuclear cells (PBMC) relative to that of unrelated healthy controls (HC). Here, using an optimized cryopreserved PBMC-based protocol, we analyzed larger RO T1D and HC cohorts. In addition, we examined T1D progression by looking at longitudinal, pre-onset and longstanding T1D samples. UPN727 cells were stimulated with autologous plasma (n=7), unrelated healthy control plasma (n=44), recent onset T1D plasma (n=46), longstanding T1D plasma (n=11), or longitudinal series plasma (n=6 time points) from pre/post onset. Gene expression analysis was performed in order to evaluate the transcriptional signature associated with T1D.

ORGANISM(S): Homo sapiens

SUBMITTER: Martin Hessner

PROVIDER: E-GEOD-35725 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:A need exists for biomarkers in T1D that can 1) sensitively and specifically detect disease-related immune activity prior to, and independent of, measurement of auto-antibodies towards islet cell antigens; 2) define immunopathological mechanisms; and 3) monitor changes in the inflammatory state associated with disease progression or response to therapeutic intervention. In an effort to fill this gap, we have applied a novel bioassay to both human and BB rat T1D whereby the complex milieu of inflammatory mediators present in plasma can be indirectly detected through their ability to drive transcription in peripheral blood mononuclear cells (PBMCs) drawn from healthy, unrelated donors. The resultant gene expressions are comprehensively measured with a microarray. In our human studies, we find that plasma of recent-onset T1D patients induces expression of a pro-inflammatory signature consisting in part of many interleukin-1 (IL-1) regulated genes related to immunological activation and immunocyte chemotaxis compared to unrelated healthy controls. This signature has been found to resolve in long-standing T1D subjects (>10 years post-onset), thus associating it with active autoimmunity. Importantly, this signature has been detected in pre-onset samples of progressors to T1D years prior to onset and prior to development of auto-antibodies directed towards islet antigens. In applying this approach to the BN rat, we observed that samples collected from both sub-strains at 60 days of age induced transcription of genes encoding cytokines, immune receptors, and signaling molecules consistent with a their shared susceptibility and immune activation. The DRlyp/lyp signature was differentiated from that of the DR+/+ by more robust induction of many interleukin (IL)-1M-bM-^@M-^Sregulated genes. Treatment of DRlyp/lyp rats with IL-1 receptor antagonist (IL-1RN) delayed onset and, in part, normalized the signature, suggesting that this approach may prove useful in monitoring the effect of therapeutic interventions in human T1D. Consistent with the presence of TREG cells in DR+/+ rats, we observed induction of a signature possessing negative regulators of transcription and inflammation. Fresh PBMCs of healthy Brown Norway (BN) rats (~180 days old males, to avoid variation introduced by estrous or pubertal status) were isolated by density gradient centrifugation. Transcription was induced by culturing PBMCs for 6 h at 37M-BM-0C in 5% CO2 with 20% allogeneic BN (healthy-unrelated control), DRlyp/lyp, or DR+/+ plasma [PMID 18209091]. DRlyp/lyp and DR+/+ Plasma was pooled at various ages (30, 40, 50, 60 days old) to represent timepoints prior to onset in the DRlyp/lyp strain.

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Transcriptional Signatures as a Disease-Specific and Predictive Inflammatory Biomarker for Type 1 Diabetes [T1D_114]

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