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.

Keywords:

• immune recognition
• allograft rejection
• MyD88
• short hairpin RNA (shRNA)
• gene delivery
• PAE

Acknowledgments

The authors gratefully acknowledge the National Natural Science Foundation of China (81102246, 51373117, and 51303126), Tianjin Natural Science Foundation (13JCZDJC33200 and 13JCQNJC11900), Doctoral Base Foundation of Educational Ministry of China (20120032110027), and Tianjin Municipal Education Commission Science Foundation (20090126).

Disclosure

The authors report no conflicts of interest in this work.