A hemodynamic response to intravenous adenovirus vector particles is caused by systemic Kupffer cell-mediated activation of endothelial cells

Publikationen: Beitrag in FachzeitschriftZeitschriftenaufsätzeForschung

AutorInnen

  • Gudrun Schiedner
  • Wilhelm Bloch
  • Sabine Hertel
  • Marion Johnston
  • Andrei Molojavyi
  • Volker Dries
  • Georg Varga
  • Nico Van Rooijen
  • Stefan Kochanek

Forschungseinrichtungen

Details

Intravascular injection of adenoviral vectors may result in a toxic and potentially lethal reaction, the mechanism of which is poorly understood. We noted that mice demonstrated a transient change in behavior that was characterized by inactivity and lethargy within minutes after intravenous injection of relatively low doses of adenoviral vectors (including high-capacity gutless vectors). Moreover, immediately after vector injection a significant drop in blood pressure was measured that most probably was caused by the systemic activation of endothelial cells as monitored by detection of phosphorylated Akt/PKB kinase, activated endothelial nitric oxide synthase (eNOS), and nitrotyrosine. The activation of the endothelium was the result of the interaction of viral particles with Kupffer cells, which are resident macrophages of the liver representing the first line of defense of the innate immune system. Surprisingly, the uptake of vector particles by Kupffer cells not only resulted in their strong activation, but also in their nearly complete disappearance from the liver. Our results suggest that the toxicity of intravenously injected adenoviral vectors may be directly linked to the activation and destruction of Kupffer cells.

OriginalspracheEnglisch
ZeitschriftHuman gene therapy
Jahrgang14
Heft17
Seiten (von - bis)1631-1641
Seitenumfang11
ISSN1043-0342
DOIs
PublikationsstatusVeröffentlicht - 20.11.2003

ID: 72215

DOI

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