title: Selective depletion or blockade of Kupffer cells leads to enhanced and prolonged hepatic transgene expression using high-capacity adenoviral vectors.
abstract: Tissue macrophages, in particular hepatic Kupffer cells (KCs), contribute to early inflammatory responses following adenoviral vector administration. This study evaluates the effect of selective and transient (3 days) depletion of KCs by a single injection of clodronate liposomes on the in vivo performance of high-capacity adenoviral (HC-Ad) vectors. In KC-depleted C57BL/6 and C3H mice increased and stabilized hAAT levels were observed following intravenous injection of HC-Ad vectors expressing human alpha-1 anti-trypsin (hAAT) either from the hAAT promoter or from the human cytomegalovirus promoter. Comparable increases in hAAT levels were obtained in mice preinjected with a transcriptionally silent HC-Ad vector. Interestingly, in the majority of animals of both strains depletion of KCs was sufficient to prevent the generation of anti-hAAT antibodies, resulting in prolonged transgene expression. Thus, short-term and selective depletion of hepatic macrophages at the same time significantly increased hepatic transgene expression and reduced the humoral immune response to the transgenic protein.
authors.affiliation: Center for Molecular Medicine, University of Cologne, Cologne, Germany. Gudrun.Schieder@medizin.uni-koeln.de
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schiedner
authors.forename: Sabine
authors.initials: S
authors.lastname: Hertel
authors.forename: Marion
authors.initials: M
authors.lastname: Johnston
authors.forename: Volker
authors.initials: V
authors.lastname: Dries
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Stefan
authors.initials: S
authors.lastname: Kochanek
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003587:Cytomegalovirus / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D007728:Kupffer Cells / Q000276:immunology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019076:Transgenes; D000515:alpha 1-Antitrypsin / Q000235:genetics
chemical_list: D000515:alpha 1-Antitrypsin