Background: Toll-like receptors (TLRs) act as initiators and conductors responsible for both innate and adaptive immune responses in 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. Concurrent gene silencing of multiple TLR adaptors, MyD88/TRIF and downstream kinases mTOR may enhance DC-mediated tolerance induction, thereby preventing graft rejection in heart transplantation.
Methods: Recipients (BALB/c) were treated with MyD88, TRIF and mTOR siRNA vectors, 3 and 7 days prior to heart transplantation and 7 and 14 days after transplantation. After siRNA treatment, recipients received a fully MHC-mismatched C57BL/6 heart. Control groups included untreated mice and the mice treated with scrambled siRNA or mTOR siRNA monotherapy.
Results: Treatment with mTOR siRNA significantly prolonged allograft survival (32.5±3.2 days) in heart transplantation. Moreover, the combination of mTOR siRNA along with MyD88 and TRIF siRNA further extended the allograft survival (89.5±5.6 days); Flow cytometric analysis showed an upregulation of FoxP3 expression in spleen lymphocytes and a concurrent downregulation of CD40, CD80 and MHC II expression in splenic dendritic cells in MyD88, TRIF and mTOR treated mice. MLR, using T cells isolated from long-survival recipients, showed a significantly decreased response to the donor original antigen. Tissue histopathology demonstrated an overall reduction in lymphocyte interstitium infiltration, hemorrhage and vasculopathy in mice treated with MyD88, TRIF and mTOR siRNA vector.
Conclusion: 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.
To cite this abstract in AMA style:Zhang X, Lian D, Zheng X, Chen D, Siu K, Johnston N, Quan D, Min W. Concurrent Silencing of TLR and Kinase Signaling Pathways To Prevent Allograft Rejection in Heart Transplantation [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/concurrent-silencing-of-tlr-and-kinase-signaling-pathways-to-prevent-allograft-rejection-in-heart-transplantation/. Accessed July 24, 2021.
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