title: Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells.
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.
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
authors.forename: Wenxian
authors.initials: W
authors.lastname: Fu
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
authors.forename: Julia
authors.initials: J
authors.lastname: Farache
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Clardy
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
authors.forename: Kimie
authors.initials: K
authors.lastname: Hattori
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Palwinder
authors.initials: P
authors.lastname: Mander
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Rioja
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016688:Mice, Inbred NOD; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C568713:GSK1210151A; D006576:Heterocyclic Compounds, 4 or More Rings; D016328:NF-kappa B
keywords: NF-KB; autoimmune diabetes; bromodomain inhibitor; immunology; mouse