Th1 cytokines are upregulated by adenoviral vectors in the brains of primed mice.
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.
Lee
Marco B
MB
University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, UK.
McMenamin
Margaret Mary
MM
Byrnes
Andrew P
AP
Charlton
Harry M
HM
Wood
Matthew J A
MJ
D000818:Animals; D046808:Atadenovirus / Q000235:genetics*; D001921:Brain / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D050483:Dopamine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D001616:beta-Galactosidase