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Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function
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 inhi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561267/ https://www.ncbi.nlm.nih.gov/pubmed/28819166 http://dx.doi.org/10.1038/s41598-017-09211-3 |
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author | Huang, Jianbing Wang, Liqing Dahiya, Satinder Beier, Ulf H. Han, Rongxiang Samanta, Arabinda Bergman, Joel Sotomayor, Eduardo M. Seto, Edward Kozikowski, Alan P. Hancock, Wayne W. |
author_facet | Huang, Jianbing Wang, Liqing Dahiya, Satinder Beier, Ulf H. Han, Rongxiang Samanta, Arabinda Bergman, Joel Sotomayor, Eduardo M. Seto, Edward Kozikowski, Alan P. Hancock, Wayne W. |
author_sort | Huang, Jianbing |
collection | PubMed |
description | 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 | Online Article Text |
id | pubmed-5561267 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-55612672017-08-21 Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function Huang, Jianbing Wang, Liqing Dahiya, Satinder Beier, Ulf H. Han, Rongxiang Samanta, Arabinda Bergman, Joel Sotomayor, Eduardo M. Seto, Edward Kozikowski, Alan P. Hancock, Wayne W. Sci Rep Article 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. Nature Publishing Group UK 2017-08-17 /pmc/articles/PMC5561267/ /pubmed/28819166 http://dx.doi.org/10.1038/s41598-017-09211-3 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Huang, Jianbing Wang, Liqing Dahiya, Satinder Beier, Ulf H. Han, Rongxiang Samanta, Arabinda Bergman, Joel Sotomayor, Eduardo M. Seto, Edward Kozikowski, Alan P. Hancock, Wayne W. Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function |
title | 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_short | Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function |
title_sort | histone/protein deacetylase 11 targeting promotes foxp3+ treg function |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561267/ https://www.ncbi.nlm.nih.gov/pubmed/28819166 http://dx.doi.org/10.1038/s41598-017-09211-3 |
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