title: Inhibition of myeloid differentiation factor 88 signaling mediated by histidine-grafted poly(β-amino ester) ester nanovector induces donor-specific liver allograft tolerance.
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.
authors.affiliation: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.
authors.forename: Fanguo
authors.initials: F
authors.lastname: Hu
authors.affiliation: School 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.
authors.forename: Hanjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: School 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.
authors.forename: Shuangnan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: School 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.
authors.forename: Yao
authors.initials: Y
authors.lastname: Peng
authors.affiliation: School 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.
authors.forename: Lin
authors.initials: L
authors.lastname: Su
authors.affiliation: School 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.
authors.forename: Jin
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
mesh_terms: D000818:Animals; D008099:Liver / Q000378:metabolism / Q000601:surgery; D016031:Liver Transplantation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D049329:Nanostructures / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D051381:Rats; D051193:Toll-Like Receptors / Q000378:metabolism; D023001:Transplantation Tolerance / Q000187:drug effects*; D014184:Transplantation, Homologous
chemical_list: D053594:Myeloid Differentiation Factor 88; D011108:Polymers; D051193:Toll-Like Receptors; C507253:poly(beta-amino ester)
keywords: MyD88; PAE; allograft rejection; gene delivery; immune recognition; short hairpin RNA (shRNA)