Local adenovirus-mediated CTLA4-immunoglobulin expression suppresses the immune responses to adenovirus vectors in the brain.
The effect of local administration of two adenovirus vectors, one of which expressed CTLA4-immunoglobulin (AdCTLA), which blocks the B7-CD28 co-stimulatory pathway of T cell activation in the inflammatory response to adenovirus vectors was investigated. Mice injected with AdCTLA and an E1-deleted adenovirus vector that encodes the lacZ gene (AdRL) into the brain showed inflammatory cell infiltration from the early phase until day 6 after injection that was not different from that seen in control mice injected with an E1-deleted adenovirus vector containing no transgene (Ad0) and AdRL. After day 6 the inflammation in the control mice increased, peaked by day 15 and then decreased gradually but persisted until day 60. By contrast, in mice treated with AdCTLA and AdRL the inflammation, especially T cell infiltration, was suppressed after day 15. The anti-adenovirus antibody titer increased gradually until day 60 in the Ad0-AdRL control group, and whereas the mice injected with AdCTLA and AdRL showed lower anti-adenovirus antibody titers than the control group mice after day 15. Neutralizing antibody was not detected in either group. Expression of beta-galactosidase, the gene product of AdRL, at the injection site in the striatum and corpus callosum peaked on day 6 and remained until day 60 although it was very low in both groups; beta-galactosidase expression was similar in the two groups in spite of the difference in the degree and extent of the local immune response in the brain. This study demonstrated that the injection of an adenovirus vector expressing CTLA4-immunoglobulin into the brain suppressed not only local cell infiltration in the brain but also reduced the humoral immune response to adenovirus vectors.
Ideguchi
M
M
Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Japan.
Kajiwara
K
K
Yoshikawa
K
K
Uchida
T
T
Ito
H
H
D000069594:Abatacept; D000256:Adenoviridae / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000276:immunology* / Q000378:metabolism*; D060908:CTLA-4 Antigen; D004338:Drug Combinations; D005822:Genetic Vectors / Q000276:immunology*; D007111:Immunity, Cellular / Q000187:drug effects; D018796:Immunoconjugates; D007136:Immunoglobulins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D001616:beta-Galactosidase / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D004338:Drug Combinations; D018796:Immunoconjugates; D007136:Immunoglobulins; D000069594:Abatacept; D001616:beta-Galactosidase