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A major disadvantage of first generation adenoviral vectors for gene therapy in the brain is the immune response they elicit. Human adenovirus is a common respiratory virus and earlier exposure to it has important implications for gene therapy. We show that the immune response against E1-deleted adenoviral vectors in the brain is more deleterious in animals previously exposed to the virus. Analysis of cytokine mRNA revealed enhanced and prolonged upregulation of the Th1 proinflammatory cytokines, IFN-gamma, TNF-alpha and IL-12 whereas, effects on Th2 cytokines were negligible. This was associated with reduced reporter gene expression, decreased expression of the dopamine transporter protein and demyelination. This knowledge of the molecular regulation of the immune response provides insight into targets, which could be manipulated to reduce inflammation in immunologically primed animals.

Original publication

DOI

10.1097/WNR.0b013e3283088e3d

Type

Journal article

Journal

Neuroreport

Publication Date

06/08/2008

Volume

19

Pages

1187 - 1192

Keywords

Animals, Atadenovirus, Brain, Cytokines, Dopamine Plasma Membrane Transport Proteins, Gene Expression Regulation, Genetic Vectors, Humans, Immunohistochemistry, Interferon-gamma, Interleukin-12, Mice, Mice, Inbred C3H, Mice, Inbred Strains, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Th1 Cells, Th2 Cells, Tumor Necrosis Factor-alpha, Up-Regulation, beta-Galactosidase