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Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways

Toll-like receptors (TLRs) act as initiators and conductors responsible for both innate and adaptive immune responses in organ transplantation. The mammalian target of rapamycin (mTOR) is one of the most critical signaling kinases that affects broad aspects of cellular functions including metabolism...

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Autores principales: Wang, Hongmei, Zhang, Xusheng, Zheng, Xiufen, Lan, Zhu, Shi, Jun, Jiang, Jifu, Zwiep, Terry, Li, Qing, Quan, Douglas, Zhang, Zhu-Xu, Min, Weiping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034230/
https://www.ncbi.nlm.nih.gov/pubmed/27659428
http://dx.doi.org/10.1038/srep33869
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author Wang, Hongmei
Zhang, Xusheng
Zheng, Xiufen
Lan, Zhu
Shi, Jun
Jiang, Jifu
Zwiep, Terry
Li, Qing
Quan, Douglas
Zhang, Zhu-Xu
Min, Weiping
author_facet Wang, Hongmei
Zhang, Xusheng
Zheng, Xiufen
Lan, Zhu
Shi, Jun
Jiang, Jifu
Zwiep, Terry
Li, Qing
Quan, Douglas
Zhang, Zhu-Xu
Min, Weiping
author_sort Wang, Hongmei
collection PubMed
description Toll-like receptors (TLRs) act as initiators and conductors responsible for both innate and adaptive immune responses in organ transplantation. The mammalian target of rapamycin (mTOR) is one of the most critical signaling kinases that affects broad aspects of cellular functions including metabolism, growth, and survival. Recipients (BALB/c) were treated with MyD88, TRIF and mTOR siRNA vectors, 3 and 7 days prior to heart transplantation and 7, 14 and 21 days after transplantation. After siRNA treatment, recipients received a fully MHC-mismatched C57BL/6 heart. Treatment with mTOR siRNA significantly prolonged allograft survival in heart transplantation. Moreover, the combination of mTOR siRNA with MyD88 and TRIF siRNA further extended the allograft survival; Flow cytometric analysis showed an upregulation of FoxP3 expression in spleen lymphocytes and a concurrent downregulation of CD40, CD86 expression, upregulation of PD-L1 expression in splenic dendritic cells in MyD88, TRIF and mTOR treated mice. There is significantly upregulated T cell exhaustion in T cells isolated from tolerant recipients. This study is the first demonstration of preventing immune rejection of allogeneic heart grafts through concurrent gene silencing of TLR and kinase signaling pathways, highlighting the therapeutic potential of siRNA in clinical transplantation.
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spelling pubmed-50342302016-09-29 Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways Wang, Hongmei Zhang, Xusheng Zheng, Xiufen Lan, Zhu Shi, Jun Jiang, Jifu Zwiep, Terry Li, Qing Quan, Douglas Zhang, Zhu-Xu Min, Weiping Sci Rep Article Toll-like receptors (TLRs) act as initiators and conductors responsible for both innate and adaptive immune responses in organ transplantation. The mammalian target of rapamycin (mTOR) is one of the most critical signaling kinases that affects broad aspects of cellular functions including metabolism, growth, and survival. Recipients (BALB/c) were treated with MyD88, TRIF and mTOR siRNA vectors, 3 and 7 days prior to heart transplantation and 7, 14 and 21 days after transplantation. After siRNA treatment, recipients received a fully MHC-mismatched C57BL/6 heart. Treatment with mTOR siRNA significantly prolonged allograft survival in heart transplantation. Moreover, the combination of mTOR siRNA with MyD88 and TRIF siRNA further extended the allograft survival; Flow cytometric analysis showed an upregulation of FoxP3 expression in spleen lymphocytes and a concurrent downregulation of CD40, CD86 expression, upregulation of PD-L1 expression in splenic dendritic cells in MyD88, TRIF and mTOR treated mice. There is significantly upregulated T cell exhaustion in T cells isolated from tolerant recipients. This study is the first demonstration of preventing immune rejection of allogeneic heart grafts through concurrent gene silencing of TLR and kinase signaling pathways, highlighting the therapeutic potential of siRNA in clinical transplantation. Nature Publishing Group 2016-09-23 /pmc/articles/PMC5034230/ /pubmed/27659428 http://dx.doi.org/10.1038/srep33869 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Wang, Hongmei
Zhang, Xusheng
Zheng, Xiufen
Lan, Zhu
Shi, Jun
Jiang, Jifu
Zwiep, Terry
Li, Qing
Quan, Douglas
Zhang, Zhu-Xu
Min, Weiping
Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways
title Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways
title_full Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways
title_fullStr Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways
title_full_unstemmed Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways
title_short Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways
title_sort prevention of allograft rejection in heart transplantation through concurrent gene silencing of tlr and kinase signaling pathways
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034230/
https://www.ncbi.nlm.nih.gov/pubmed/27659428
http://dx.doi.org/10.1038/srep33869
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