title: Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors.
abstract: Adeno-associated viral vectors (rAAV) are frequently used in gene therapy trials. Although rAAV vectors are of low immunogenicity, humoral as well as T cell responses may be induced. While the former limits vector reapplication, the expansion of cytotoxic T cells correlates with liver inflammation and loss of transduced hepatocytes. Because adaptive immune responses are a consequence of recognition by the innate immune system, we aimed to characterize cell autonomous immune responses elicited by rAAV in primary human hepatocytes and nonparenchymal liver cells. Surprisingly, Kupffer cells, but also liver sinusoidal endothelial cells, mounted responses to rAAV, whereas neither rAAV2 nor rAAV8 were recognized by hepatocytes. Viral capsids were sensed at the cell surface as pathogen-associated molecular patterns by Toll-like receptor 2. In contrast to the Toll-like receptor 9-mediated recognition observed in plasmacytoid dendritic cells, immune recognition of rAAV in primary human liver cells did not induce a type I interferon response, but up-regulated inflammatory cytokines through activation of nuclear factor κB.
  
  
  CONCLUSIONS
  Using primary human liver cells, we identified a novel mechanism of rAAV recognition in the liver, demonstrating that alternative means of sensing rAAV particles have evolved. Minimizing this recognition will be key to improving rAAV-mediated gene transfer and reducing side effects in clinical trials due to immune responses against rAAV.
authors: Department I of Internal Medicine, University of Cologne, Cologne, Germany.
authors: Marianna
authors: M
authors: Hösel
authors: Mathias
authors: M
authors: Broxtermann
authors: Hanna
authors: H
authors: Janicki
authors: Knud
authors: K
authors: Esser
authors: Silke
authors: S
authors: Arzberger
authors: Pia
authors: P
authors: Hartmann
authors: Sonja
authors: S
authors: Gillen
authors: Jörg
authors: J
authors: Kleeff
authors: Dirk
authors: D
authors: Stabenow
authors: Margarete
authors: M
authors: Odenthal
authors: Percy
authors: P
authors: Knolle
authors: Michael
authors: M
authors: Hallek
authors: Ulrike
authors: U
authors: Protzer
authors: Hildegard
authors: H
authors: Büning
mesh_terms: D001706:Biopsy; D002213:Capsid / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology / Q000821:virology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000276:immunology*; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007728:Kupffer Cells / Q000166:cytology / Q000276:immunology / Q000821:virology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D016207:Cytokines; D016328:NF-kappa B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2