Rapid Kupffer cell death after intravenous injection of adenovirus vectors.
When adenovirus vectors are injected intravenously, they are quickly taken up by Kupffer cells in the liver. We report that this causes rapid necrosis of Kupffer cells in mice at doses of 10(11) particles/kg or higher. By 10 min after intravenous vector injection, Kupffer cells were permeable to propidium iodide and trypan blue. This coincided with a sharp rise in serum lactate dehydrogenase. Ultrastructural examination showed degeneration of Kupffer cells, including complete disappearance of chromatin by 1 h. After an initial intravenous injection of vector, dead Kupffer cells were unable to take up a second dose of vector, and hepatic transgene expression from the second dose was augmented. Death of Kupffer cells did not affect serum levels of IL-6 or IL-12. There was no immediate change in the number of Kupffer cells in the liver, but a significant decline was found by 4 h after injection of vector. Interestingly, substantial numbers of vector-containing Kupffer cells were found in pulmonary capillaries, indicating that they had been swept out of the liver. Together these results show that an intravenous injection of adenovirus vector causes synchronous and surprisingly rapid Kupffer cell death.
Manickan
Elanchezhiyan
E
Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Smith
Jeffrey S
JS
Tian
Jie
J
Eggerman
Thomas L
TL
Lozier
Jay N
JN
Muller
Jacqueline
J
Byrnes
Andrew P
AP
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002843:Chromatin / Q000378:metabolism / Q000648:ultrastructure; D004396:Coloring Agents; D005822:Genetic Vectors / Q000008:administration & dosage; D007113:Immunity, Innate; D007275:Injections, Intravenous; D018664:Interleukin-12 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007728:Kupffer Cells / Q000473:pathology* / Q000648:ultrastructure; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000473:pathology / Q000648:ultrastructure; D008168:Lung / Q000098:blood supply / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009336:Necrosis; D011419:Propidium; D014343:Trypan Blue
D002843:Chromatin; D004396:Coloring Agents; D015850:Interleukin-6; D018664:Interleukin-12; D011419:Propidium; D007770:L-Lactate Dehydrogenase; D014343:Trypan Blue