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- W2050346325 abstract "Non human primate (NHP) derived adenoviral vectors are currently being pursed as candidate vectors for vaccination in individuals with prior exposure to human adenoviruses. In the present study we monitored toxicity at different times following high dose systemic administration of NHP adenoviruses (AdC6, AdC7 and AdC9) to C57BL/6 mice. Vector administrations were usually accompanied by a transient leukopenia and thrombocytopenia that resolved by day 14. Hematoxylin and eosin staining of various tissues indicated presence of infiltrates primarily in the liver. In addition, serum alanine amino transferase (ALT) and aspartate amino transferase (AST) levels were elevated. However, vectors could be detected in a variety of tissues including liver, spleen, lung and bone marrow. Pro-inflammatory cytokines – notably IFN-α, IL-6, TNF-α and KC – were elevated within 2 hrs of vector administration and started to decline to baseline levels by 24 hrs. The profile and magnitude of cytokines induced by the NHP adenoviruses were different when compared to human Ad5. In particular, the levels of IL-6, TNF-α and IFN-α were substantially higher with NHP adenoviruses than with human Ad5. The increased activation of innate immunity observed with the NHP adenoviruses in mice was studied in vitro with two different types of human dendritic cells, monocytoid and plasmacytoid. In each case, the NHP adenoviruses resulted in increased production of inflammatory cytokines as compared to what was seen with human Ad5. Additional studies were performed in knockout mice (MyD88 KO and type I interferon receptor KO) to better understand the mechanisms that lead to the brisk activation of innate immunity with NHP adenoviruses. These studies suggest that NHP adenoviruses initiate an autocatalytic type I interferon response that augments the secretion of TNF-α and IL-6. The cellular receptors and signaling pathways responsible for these effects are under investigation." @default.
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- W2050346325 date "2006-01-01" @default.
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- W2050346325 title "609. Acute-Phase Toxicity Following Systemic Administration of Non-Human Primate Derived Adenoviral Vectors to Mice" @default.
- W2050346325 doi "https://doi.org/10.1016/j.ymthe.2006.08.683" @default.
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