Activation of innate immunity in nonhuman primates following intraportal administration of adenoviral vectors.
The innate immune response to intraportally infused adenoviral vector was evaluated in rhesus monkeys. A first-generation adenovirus-expressing lacZ (Ad-lacZ) was administered at a dose just below that which causes severe morbidity. The response to vector was evaluated for the initial 24 h following infusion. Clinical findings during this time were primarily limited to petechiae, consistent with the development of thrombocytopenia and biochemical evidence of disseminated intravascular coagulation. Serum transaminases were elevated and a lymphopenia developed. Tracking of fluorescent-labeled vector demonstrated distribution to macrophages and dendritic cells of the spleen and Kupffer cells of the liver. A systemic release of the cytokine IL-6 occurred soon after vector infusion. Analysis of splenic cells revealed acute activation of macrophages and dendritic cells followed by massive apoptosis. Bone marrow cultures demonstrated normal erythroid and primitive progenitors with a significant decrease in myeloid progenitors. Similar findings, except the abnormality in bone marrow cultures, were observed in monkeys who received an identical dose of Ad-lacZ in which vector genes were inactivated with psoralen and UV irradiation. These data suggest that inadvertent targeting of antigen-presenting cells following intraportal infusion of vector leads to a systemic cytokine syndrome which may be triggered by the viral capsid proteins.
Schnell
M A
MA
Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia, PA 19104, USA.
Zhang
Y
Y
Tazelaar
J
J
Gao
G P
GP
Yu
Q C
QC
Qian
R
R
Chen
S J
SJ
Varnavski
A N
AN
LeClair
C
C
Raper
S E
SE
Wilson
J M
JM
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D005363:Ficusin / Q000494:pharmacology; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000494:pharmacology; D005822:Genetic Vectors; D015850:Interleukin-6 / Q000096:biosynthesis; D007728:Kupffer Cells / Q000378:metabolism; D007763:Lac Operon; D008099:Liver / Q000378:metabolism; D008231:Lymphopenia; D008253:Macaca mulatta; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008747:Methylcellulose / Q000378:metabolism; D008854:Microscopy, Electron; D008954:Models, Biological; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013921:Thrombocytopenia; D013997:Time Factors; D014018:Tissue Distribution; D000637:Transaminases / Q000096:biosynthesis; D014466:Ultraviolet Rays; D001616:beta-Galactosidase / Q000378:metabolism
D005456:Fluorescent Dyes; D015850:Interleukin-6; D008747:Methylcellulose; D000637:Transaminases; D001616:beta-Galactosidase; D005363:Ficusin