Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
Clardy, Susan M
Prinjha, Rab K
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CitationFu, W., J. Farache, S. M. Clardy, K. Hattori, P. Mander, K. Lee, I. Rioja, et al. 2014. “Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells.” eLife 3 (1): e04631. doi:10.7554/eLife.04631. http://dx.doi.org/10.7554/eLife.04631.
AbstractEpigenetic 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. DOI: http://dx.doi.org/10.7554/eLife.04631.001
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:13890767
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