Reference - Detail
|Author||Shayakhmetov DM, Li ZY, Ni S, Lieber A.|
|Title||Interference with the IL-1-signaling pathway improves the toxicity profile of systemically applied adenovirus vectors.|
The safety of gene therapy vectors is a major concern when novel viral or nonviral therapeutics are proposed for applications in humans. Adenovirus (Ad) vectors have been extensively used as efficient gene delivery vehicles in vitro over the last two decades. However, upon i.v. application, they elicit robust innate and inflammatory responses that may be fatal for the host. To date, the primary cytokines and chemokines involved in the initiation of these host responses remain illusive. In this study, we demonstrate that IL-1 is a major mediator involved in the initiation of immediate host responses toward i.v. applied Ad vectors. Using mice in which IL-1 signaling was genetically eliminated (IL-1RI-KO), or wild-type animals for which signaling was blocked by anti-IL-1 Abs, we found that i.v. applied Ad vectors elicited dramatically reduced acute inflammatory responses when compared with control animals. Importantly, the efficiency of Ad gene transfer in vivo was not significantly affected by interfering with IL-1 signaling. Using an in situ hybridization technique, we found that hepatocytes and Kupffer cells trigger IL-1 transcription in liver tissue after i.v. Ad vector administration. We also found that expression of the MIP-2 chemokine gene (which is responsible for recruitment of neutrophils to the liver) depends on IL-1 activation. Our data indicate that immediate innate and inflammatory host responses toward i.v. applied Ad vectors can be pharmacologically controlled through interference with IL-1 signaling pathways.
|Description||in situハイブリダイゼーションを用いたIL-1α 遺伝子の転写解析を行うための蛍光プローブの作製に使用されました。|
|MeSH||Adenoviruses, Human / genetics* Adenoviruses, Human / immunology* Animals Chemokines / biosynthesis Chemokines / genetics Cytokines / biosynthesis Cytokines / genetics Gene Expression Regulation / immunology Gene Transfer Techniques Genetic Vectors / administration & dosage Genetic Vectors / immunology Genetic Vectors / toxicity* Inflammation Mediators / administration & dosage Inflammation Mediators / immunology Inflammation Mediators / toxicity Injections, Intravenous Interleukin-1 / antagonists & inhibitors Interleukin-1 / biosynthesis Interleukin-1 / genetics Interleukin-1 / physiology* Kupffer Cells / immunology Kupffer Cells / metabolism Kupffer Cells / virology Liver / immunology* Liver / metabolism Liver / virology* Mice Mice, Inbred C57BL Mice, Knockout Receptors, Interleukin-1 / deficiency Receptors, Interleukin-1 / genetics Receptors, Interleukin-1 / physiology Signal Transduction / genetics Signal Transduction / immunology* Tumor Necrosis Factor-alpha / physiology Up-Regulation / genetics Up-Regulation / immunology|
|DNA material||pCAmsIL1 alpha (RDB01516)|