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Elife. 2014 Nov 19;3:e04631. doi: 10.7554/eLife.04631.

Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells.

Author information

1
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
2
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
3
Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage, United Kingdom.

Abstract

Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing transcriptional regulators, irreversibly suppressed development of type-1 diabetes in NOD mice. The inhibitor could prevent or clear insulitis, but had minimal influence on the transcriptomes of infiltrating and circulating T cells. Rather, it induced pancreatic macrophages to adopt an anti-inflammatory phenotype, impacting the NF-κB pathway in particular. I-BET151 also elicited regeneration of islet β-cells, inducing proliferation and expression of genes encoding transcription factors key to β-cell differentiation/function. The effect on β cells did not require T cell infiltration of the islets. Thus, treatment with I-BET151 achieves a 'combination therapy' currently advocated by many diabetes investigators, operating by a novel mechanism that coincidentally dampens islet inflammation and enhances β-cell regeneration.

KEYWORDS:

NF-KB; autoimmune diabetes; bromodomain inhibitor; immunology; mouse

PMID:
25407682
PMCID:
PMC4270084
DOI:
10.7554/eLife.04631
[Indexed for MEDLINE]
Free PMC Article

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