title: Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways.
abstract: 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.
authors.affiliation: Institute of Immunotherapy and Medical College of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China.|Department of Surgery, Pathology, and Oncology, University of Western Ontario, London, Canada.|Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Surgery, Pathology, and Oncology, University of Western Ontario, London, Canada.|Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada.
authors.forename: Xusheng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Pathology, and Oncology, University of Western Ontario, London, Canada.|Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada.
authors.forename: Xiufen
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Lan
authors.affiliation: Institute of Immunotherapy and Medical College of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.affiliation: Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada.
authors.forename: Jifu
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Surgery, Pathology, and Oncology, University of Western Ontario, London, Canada.|Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada.
authors.forename: Terry
authors.initials: T
authors.lastname: Zwiep
authors.affiliation: Institute of Immunotherapy and Medical College of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China.|Department of Surgery, Pathology, and Oncology, University of Western Ontario, London, Canada.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Surgery, Pathology, and Oncology, University of Western Ontario, London, Canada.|Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada.
authors.forename: Douglas
authors.initials: D
authors.lastname: Quan
authors.affiliation: Institute of Immunotherapy and Medical College of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China.|Department of Surgery, Pathology, and Oncology, University of Western Ontario, London, Canada.|Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada.
authors.forename: Zhu-Xu
authors.initials: ZX
authors.lastname: Zhang
authors.affiliation: Institute of Immunotherapy and Medical College of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China.|Department of Surgery, Pathology, and Oncology, University of Western Ontario, London, Canada.|Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada.
authors.forename: Weiping
authors.initials: W
authors.lastname: Min