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

ABSTRACT: The dilute plasma cytokine milieu associated with type 1 diabetes (T1D), while difficult to measure directly, is sufficient to drive transcription in a bioassay that uses healthy leukocytes as reporters. Previously, we reported disease-associated, partially IL-1 dependent, transcriptional signatures in both T1D patients and the BioBreeding (BB) rat model. Here, we examine temporal signatures in congenic BBDR.lyp/lyp rats that develop spontaneous T1D, and BBDR rats where T1D progresses only after immunological perturbation in young animals. After weaning, the BBDR temporal signature showed early coincident induction of transcription related to innate inflammation as well as IL-10- and TGF-?-mediated regulation. BBDR plasma cytokine levels mirrored the signatures showing early inflammation, followed by induction of a regulated state that correlated with failure of virus to induce T1D in older rats. In contrast, the BBDR.lyp/lyp temporal signature exhibited asynchronous dynamics, with delayed induction of inflammatory transcription and later, weaker induction of regulatory transcription, consistent with their deficiency in regulatory T cells. Through longitudinal analyses of plasma-induced signatures in BB rats and a human T1D progressor, we have identified changes in immunoregulatory processes that attenuate a preexisting innate inflammatory state in BBDR rats, suggesting a mechanism underlying the decline in T1D susceptibility with age.

SUBMITTER: Chen YG

PROVIDER: S-EPMC4027975 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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

Chen Y G YG Mordes J P JP Blankenhorn E P EP Kashmiri H H Kaldunski M L ML Jia S S Geoffrey R R Wang X X Hessner M J MJ

Genes and immunity 20130606 6

The dilute plasma cytokine milieu associated with type 1 diabetes (T1D), while difficult to measure directly, is sufficient to drive transcription in a bioassay that uses healthy leukocytes as reporters. Previously, we reported disease-associated, partially IL-1 dependent, transcriptional signatures in both T1D patients and the BioBreeding (BB) rat model. Here, we examine temporal signatures in congenic BBDR.lyp/lyp rats that develop spontaneous T1D, and BBDR rats where T1D progresses only after ...[more]

PMID: 23739610

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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)-1–regulated 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.

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

Publications

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

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