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

  1. Wenxian Fu
  2. Julia Farache
  3. Susan M Clardy
  4. Kimie Hattori
  5. Palwinder Mander
  6. Kevin Lee
  7. Inmaculada Rioja
  8. Ralph Weissleder
  9. Rab K Prinjha
  10. Christophe Benoist
  11. Diane Mathis  Is a corresponding author
  1. University of California, San Diego, United States
  2. Harvard Medical School, United States
  3. Massachusetts General Hospital, Harvard Medical School, United States
  4. GlaxoSmithKline, United Kingdom
  5. Pfizer, United States
Research Article
  • Cited 49
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Cite this article as: eLife 2014;3:e04631 doi: 10.7554/eLife.04631

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.

Article and author information

Author details

  1. Wenxian Fu

    University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  2. Julia Farache

    Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  3. Susan M Clardy

    Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  4. Kimie Hattori

    Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  5. Palwinder Mander

    GlaxoSmithKline, Stevenage, United Kingdom
    Competing interests
    Palwinder Mander, GlaxoSmithKline has an ongoing interest in the therapeutic applications of BET-protein inhibitors.
  6. Kevin Lee

    Pfizer, Cambridge, United States
    Competing interests
    Kevin Lee, GlaxoSmithKline has an ongoing interest in the therapeutic applications of BET-protein inhibitors.
  7. Inmaculada Rioja

    GlaxoSmithKline, Stevenage, United Kingdom
    Competing interests
    Inmaculada Rioja, GlaxoSmithKline has an ongoing interest in the therapeutic applications of BET-protein inhibitors..
  8. Ralph Weissleder

    Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  9. Rab K Prinjha

    GlaxoSmithKline, Stevenage, United Kingdom
    Competing interests
    Rab K Prinjha, GlaxoSmithKline has an ongoing interest in the therapeutic applications of BET-protein inhibitors.
  10. Christophe Benoist

    Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  11. Diane Mathis

    Harvard Medical School, Boston, United States
    For correspondence
    diane_mathis@hms.harvard.edu
    Competing interests
    Diane Mathis, Reviewing editor, eLife.

Ethics

Animal experimentation: NOD/Lt mice were bred under specific-pathogen-free conditions in our animal facility at the New Research Building of Harvard Medical School, cared for in accordance with the ethical guidelines of the Institutional Animal Care and Use Committee (#02954). Relevant studies were also conducted in accordance with GSK's Policy on the Care, Welfare and Treatment of Laboratory Animals. NOD.Cg-Rag1<tm1mom> mice were maintained in our lab's colony at Jackson Laboratory.

Reviewing Editor

  1. Shimon Sakaguchi, Osaka University, Japan

Publication history

  1. Received: September 5, 2014
  2. Accepted: November 19, 2014
  3. Accepted Manuscript published: November 19, 2014 (version 1)
  4. Version of Record published: December 30, 2014 (version 2)

Copyright

© 2014, Fu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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