IMMUNE-RESPONSES TO ADENOVIRAL VECTORS DURING GENE-TRANSFER IN THE BRAIN

We have investigated the immune response to El-deleted adenovirus vect ors encoding the lacZ gene introduced into the brains of adult mice. I njection of these nonreplicating vectors caused a marked inflammatory response in the brain as assessed by immunocytochemistry and flow cyto metry of leukocytes. Infiltrating leukocytes were detectable within 2 days of injection and reached a maximum by 9 days. Thereafter, the num ber of infiltrating cells decreased, but a small number persisted in t he brain until day 60. Between 2 and 4 days after injection, the perce ntage of CD8(+) cells detectable increased whereas the percentage of C D4(+) cells present in the infiltrating population did not significant ly 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 b eta-Gal(+) cells was still seen at 60 days after injection. This study demonstrates that a quantitative analysis of the immune responses cau sed by a nonreplicating adenovirus vector is possible in the brain. El -deleted adenoviral vectors trigger a strong inflammatory response in the brain, but this immune response is not sufficient to eliminate com pletely expression of genes encoded by the adenoviral construct.