Lipidoid Nanoparticles Containing PD-L1 siRNA Delivered In Vivo Enter Kupffer Cells and Enhance NK and CD8+ T Cell-mediated Hepatic Antiviral Immunity

Molecular Therapy: Nucleic Acids

Tuyen M Nguyen¹  Tatiana I Novobrantseva¹  Sun-Sang J Sung²  Joseph S Dolina³  Young S Hahn³ 

[1] Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA;Department of Medicine, Center for Inflammation and Regeneration, University of Virginia, Charlottesville, Virginia, USA;Department of Microbiology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA;

关键词: lipidoid nanoparticles;    NK cells;    nucleic acid therapeutics;    PD-L1;    T cells;   

DOI  :  10.1038/mtna.2012.63

来源: DOAJ

【 摘 要 】

Effective clinical application of antiviral immunotherapies necessitates enhancing the functional state of natural killer (NK) and CD8+ T cells. An important mechanism for the establishment of viral persistence in the liver is the activation of the PD-1/PD-L1 inhibitory pathway. To examine the role of hepatic myeloid PD-L1 expression during viral infection, we determined the magnitude and quality of antiviral immune responses by administering PD-L1 short-interfering RNA (siRNA) encapsulated in lipidoid nanoparticles (LNP) in mice. Our studies indicate that Kupffer cells (KC) preferentially engulfed PD-L1 LNP within a short period of time and silenced Pdl1 during adenovirus and MCMV infection leading to enhanced NK and CD8+ T cell intrahepatic accumulation, effector function (interferon (IFN)-γ and granzyme B (GrB) production), CD8+ T cell–mediated viral clearance, and memory. Our results demonstrate that PD-L1 knockdown on KCs is central in determining the outcome of liver viral infections, and they represent a new class of gene therapy.

【 授权许可】

Unknown