Immune responses to adenoviral vectors during gene transfer in the brain.
We have investigated the immune response to E1-deleted adenovirus vectors encoding the lacZ gene introduced into the brains of adult mice. Injection of these nonreplicating vectors caused a marked inflammatory response in the brain as assessed by immunocytochemistry and flow cytometry of leukocytes. Infiltrating leukocytes were detectable within 2 days of injection and reached a maximum by 9 days. Thereafter, the number of infiltrating cells decreased, but a small number persisted in the brain until day 60. Between 2 and 4 days after injection, the percentage of CD8+ cells detectable increased whereas the percentage of CD4+ cells present in the infiltrating population did not significantly increase until day 6, peaking on day 15. Activated CD25+ T cells were detectable between days 6 and 15. beta-Galactosidase (beta-Gal), the product of the lacZ gene encoded by the vector, was also detected, both at the injection site in the striatum and also in the substantia nigra. Expression peaked between 4 and 6 days but a small number of beta-Gal+ cells was still seen at 60 days after injection. This study demonstrates that a quantitative analysis of the immune responses caused by a nonreplicating adenovirus vector is possible in the brain. E1-deleted adenoviral vectors trigger a strong inflammatory response in the brain, but this immune response is not sufficient to eliminate completely expression of genes encoded by the adenoviral construct.
Kajiwara
K
K
Nuffield Department of Surgery, University of Oxford, Johm Radcliffe Hospital, UK.
Byrnes
A P
AP
Charlton
H M
HM
Wood
M J
MJ
Wood
K J
KJ
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D001921:Brain / Q000276:immunology* / Q000473:pathology; D001923:Brain Chemistry; D005434:Flow Cytometry; D018014:Gene Transfer Techniques / Q000009:adverse effects; D005822:Genetic Vectors / Q000276:immunology*; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007249:Inflammation / Q000473:pathology; D007763:Lac Operon / Q000276:immunology; D007962:Leukocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H