Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways
| Autor: | Jun Shi, Terry Zwiep, Xusheng Zhang, Xiufen Zheng, Qing Li, Jifu Jiang, Hongmei Wang, Zhu Lan, Zhu-Xu Zhang, Wei-Ping Min, Douglas Quan |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Heart transplantation Multidisciplinary medicine.medical_treatment T cell Biology Article 3. Good health Transplantation 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Immune system medicine.anatomical_structure Downregulation and upregulation TRIF Immunology Cancer research medicine Gene silencing PI3K/AKT/mTOR pathway 030215 immunology |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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