Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function

Abstract Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacety...

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Autores principales:	Jianbing Huang, Liqing Wang, Satinder Dahiya, Ulf H. Beier, Rongxiang Han, Arabinda Samanta, Joel Bergman, Eduardo M. Sotomayor, Edward Seto, Alan P. Kozikowski, Wayne W. Hancock
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5a235acd97ca4a28899dd27f87d82b68
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spelling	oai:doaj.org-article:5a235acd97ca4a28899dd27f87d82b682021-12-02T11:52:31ZHistone/protein deacetylase 11 targeting promotes Foxp3+ Treg function10.1038/s41598-017-09211-32045-2322https://doaj.org/article/5a235acd97ca4a28899dd27f87d82b682017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09211-3https://doaj.org/toc/2045-2322Abstract Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-β. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases.Jianbing HuangLiqing WangSatinder DahiyaUlf H. BeierRongxiang HanArabinda SamantaJoel BergmanEduardo M. SotomayorEdward SetoAlan P. KozikowskiWayne W. HancockNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jianbing Huang Liqing Wang Satinder Dahiya Ulf H. Beier Rongxiang Han Arabinda Samanta Joel Bergman Eduardo M. Sotomayor Edward Seto Alan P. Kozikowski Wayne W. Hancock Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function
description	Abstract Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-β. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases.
format	article
author	Jianbing Huang Liqing Wang Satinder Dahiya Ulf H. Beier Rongxiang Han Arabinda Samanta Joel Bergman Eduardo M. Sotomayor Edward Seto Alan P. Kozikowski Wayne W. Hancock
author_facet	Jianbing Huang Liqing Wang Satinder Dahiya Ulf H. Beier Rongxiang Han Arabinda Samanta Joel Bergman Eduardo M. Sotomayor Edward Seto Alan P. Kozikowski Wayne W. Hancock
author_sort	Jianbing Huang
title	Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function
title_short	Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function
title_full	Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function
title_fullStr	Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function
title_full_unstemmed	Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function
title_sort	histone/protein deacetylase 11 targeting promotes foxp3+ treg function
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/5a235acd97ca4a28899dd27f87d82b68
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Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function

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