| HIV-1-derived lentiviral vectors directly activate plasmacytoid dendritic cells, which in turn induce the maturation of myeloid dendritic cells. | |
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MedLine Citation:
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PMID: 20825284 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Lentiviral vectors (LV) can induce type I interferon (IFN I) production from murine plasmacytoid dendritic cells (pDC), but not myeloid (my)DC. Here, we investigated whether this mechanism is conserved in human DC. MyDC and pDC were isolated from peripheral blood and transduced with increasing vector concentrations. Compared with in vitro differentiated monocyte-derived DC, the transduction efficiency of peripheral blood DC was low (ranging from <1% to 45%), with pDC showing the lowest susceptibility to LV transduction. Phenotype and function of myDC were not directly modified by LV transduction; by contrast, pDC produced significant levels of IFN-α and tumor necrosis factor-α. pDC activation was dependent on functional vector particles and was mediated by Toll-like receptor 7/9 triggering. Coculture of myDC with pDC in the presence of LV resulted in myDC activation, with CD86 up-regulation and interleukin-6 secretion. These findings demonstrate that the induction of transgene-specific immunity is triggered by an innate immune response with pDC activation and consequent myDC maturation, a response that closely resembles the one induced by functional viruses. This information is important to design strategies aimed at using LV in humans for gene therapy, where adverse immune responses must be avoided, or for cancer immunotherapy, where inducing immunity is the goal. |
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Authors:
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Maura Rossetti; Silvia Gregori; Ehud Hauben; Brian D Brown; Lucia Sergi Sergi; Luigi Naldini; Maria-Grazia Roncarolo |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-01-14 |
Journal Detail:
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Title: Human gene therapy Volume: 22 ISSN: 1557-7422 ISO Abbreviation: Hum. Gene Ther. Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-02-18 Completed Date: 2011-06-09 Revised Date: 2011-11-24 |
Medline Journal Info:
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Nlm Unique ID: 9008950 Medline TA: Hum Gene Ther Country: United States |
Other Details:
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Languages: eng Pagination: 177-88 Citation Subset: IM |
Affiliation:
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San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) , Department of Regenerative Medicine, Stem Cells and Gene Therapy, Via Olgettina 58, Milan, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cells, Cultured Dendritic Cells / cytology*, metabolism* Genetic Vectors* HIV-1 / genetics* Humans Immunity, Innate Interferon-alpha / secretion Interleukin-6 / secretion Monocytes / cytology Myeloid Cells / metabolism* Toll-Like Receptor 7 / immunology Toll-Like Receptor 9 / immunology Tumor Necrosis Factor-alpha / secretion Up-Regulation |
| Grant Support | |
ID/Acronym/Agency:
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TGT06E02//Telethon |
| Chemical | |
Reg. No./Substance:
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0/Interferon-alpha; 0/Interleukin-6; 0/TLR7 protein, human; 0/TLR9 protein, human; 0/Toll-Like Receptor 7; 0/Toll-Like Receptor 9; 0/Tumor Necrosis Factor-alpha |
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