Fu Wenxian, Farache Julia, Clardy Susan M, Hattori Kimie, Mander Palwinder, Lee Kevin, Rioja Inmaculada, Weissleder Ralph, Prinjha Rab K, Benoist Christophe, Mathis Diane
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
Elife. 2014 Nov 19;3:e04631. doi: 10.7554/eLife.04631.
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.
表观遗传修饰剂是一类新兴的抗肿瘤药物，在多种癌症背景下都具有强大的作用。它们对自发发展的自身免疫性疾病的影响尚未得到充分研究。我们报告称，用I-BET151（一种含溴结构域的转录调节因子家族的小分子抑制剂）进行短期治疗，可不可逆地抑制NOD小鼠1型糖尿病的发展。该抑制剂可以预防或消除胰岛炎，但对浸润和循环T细胞的转录组影响极小。相反，它诱导胰腺巨噬细胞采用抗炎表型，尤其影响NF-κB通路。I-BET151还引发胰岛β细胞的再生，诱导增殖并表达编码对β细胞分化/功能至关重要的转录因子的基因。对β细胞的作用并不需要T细胞浸润胰岛。因此，用I-BET151进行治疗实现了目前许多糖尿病研究人员所倡导的“联合疗法”通过一种新机制发挥作用，该机制恰好能减轻胰岛炎症并增强β细胞再生。
