組蛋白去乙酰酶(HDAC)抑制劑是美國食品和藥物管理局FDA批準(zhǔn)的一種癌癥治療藥物,，Wayne Hancock和同事卻發(fā)現(xiàn)，這種藥物還可能抑制過度的免疫反應(yīng),，這一最新的研究成果發(fā)表在11月號的《自然—醫(yī)學(xué)》期刊上,。
免疫系統(tǒng)的過度反應(yīng)會導(dǎo)致一系列的問題，如炎癥性腸病和對移植器官的排斥,。Hancock和同事發(fā)現(xiàn),，HDAC抑制劑能夠激活調(diào)控性T細(xì)胞，這種細(xì)胞因為能抑制其他的免疫反應(yīng),，因而也被稱為抑制性T細(xì)胞,。因此，HDAC抑制劑降低了炎癥性腸病的癥狀,，并能預(yù)防對心臟和胰腺移植的排斥,。
新發(fā)現(xiàn)預(yù)測，HDAC抑制劑也許還能對付與免疫活性相關(guān)的疾病,，如多發(fā)性硬化癥等自體免疫性疾病,。（科學(xué)時報）
原始出處:
Nature Medicine
Published online: 7 October 2007 | doi:10.1038/nm1652
Deacetylase inhibition promotes the generation and function of regulatory T cells
Ran Tao1, Edwin F de Zoeten2,3, Engin Özkaynak1,4, Chunxia Chen1, Liqing Wang1, Paige M Porrett3, Bin Li4, Laurence A Turka3, Eric N Olson5, Mark I Greene4, Andrew D Wells1,4 & Wayne W Hancock1,4
Histone/protein deacetylases (HDACs) regulate chromatin remodeling and gene expression as well as the functions of more than 50 transcription factors and nonhistone proteins. We found that administration of an HDAC inhibitor (HDACi) in vivo increased Foxp3 gene expression, as well as the production and suppressive function of regulatory T cells (Treg cells). Although Treg cells express multiple HDACs, HDAC9 proved particularly important in regulating Foxp3-dependent suppression. Optimal Treg function required acetylation of several lysines in the forkhead domain of Foxp3, and Foxp3 acetylation enhanced binding of Foxp3 to the Il2 promoter and suppressed endogenous IL-2 production. HDACi therapy in vivo enhanced Treg-mediated suppression of homeostatic proliferation, decreased inflammatory bowel disease through Treg-dependent effects, and, in conjunction with a short course of low-dose rapamycin, induced permanent, Treg-dependent cardiac and islet allograft survival and donor-specific allograft tolerance. Our data show that use of HDACi allows the beneficial pharmacologic enhancement of both the numbers and suppressive function of Foxp3+ Treg cells.
Division of Transplantation Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Studies of Pediatric Liver Diseases, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4318, USA.
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4318, USA.
Department of Medicine, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-6082, USA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-6082, USA.
Department of Molecular Biology,University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Correspondence to: Wayne W Hancock1,4 e-mail: [email protected]
