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Inhibition of myeloid differentiation factor 88 signaling mediated by histidine-grafted poly(β-amino ester) ester nanovector induces donor-specific liver allograft tolerance

Authors Hu F, Wang H, Zhang S, Peng Y, Su L, Chang J, Liu G

Received 23 January 2015

Accepted for publication 28 March 2015

Published 6 July 2015 Volume 2015:10(1) Pages 4367—4382

DOI https://doi.org/10.2147/IJN.S81413

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Lei Yang

Fanguo Hu,1,* Hanjie Wang,2,* Shuangnan Zhang,2 Yao Peng,2 Lin Su,2 Jin Chang,2 Gang Liu1

1Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2School of Life Sciences, Tianjin University, Collaborative Innovation Center of Chemical Science and Engineering, Tianjin Engineering Center of Micro-Nano Biomaterials and Detection-Treatment Technology, Tianjin, People’s Republic of China

*These authors contributed equally to this work

Abstract: Toll-like receptors (TLRs) activate biochemical pathways that evoke activation of innate immunity, which leads to dendritic cell maturation and initiation of adaptive immune responses that provoke allograft rejection. We aimed to prolong allograft survival by selectively inhibiting expression of myeloid differentiation factor 88 (MyD88), which is an essential adaptor in TLR signaling. We designed and synthesized a novel histidine-grafted poly(β-amino ester)(HGPAE) nanovector, which was shown to be safe and efficient both in vitro and in vivo for the delivery of a plasmid containing shRNA targeting MyD88 (pMyD88). We also demonstrated that the pMyD88/HGPAE complex mediated remarkable inhibition of MyD88 expression in rat liver in vivo. We transplanted Dark Agouti rat livers lacking MyD88 as result of transfection with the pMyD88/HGPAE complex into Lewis rats. The recipients survived longer and graft rejection of the donor liver as well as serum levels of IL-2 and IFN-γ in the recipient were significantly reduced.

Keywords: immune recognition, allograft rejection, MyD88, short hairpin RNA (shRNA), gene delivery, PAE

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