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Development of a Langerhans cell-targeted gene therapy format using a dendritic cell-specific promoter

Abstract

Langerhans cells (LC), which are a skin-specific member of the dendritic cell (DC) family of antigen presenting cells, play critical roles in the initiation of cellular immune responses in the skin. We developed a LC-targeted gene therapy format in this study, aimed at the establishment of in situ protocols for genetic manipulation of LC function. Dectin-2 is a unique C-type lectin that is expressed selectively by DC, including epidermal LC. A 3.2 kb 5′ flanking fragment isolated from the mouse dectin-2 gene, termed the dectin-2 promoter (pDec2), exhibited significant transcriptional activities in epidermal-derived DC lines of the XS series, but not in any of the tested non-DC lines. When pDec2-driven luciferase gene (pDec2-Luc) or enhanced green fluorescence protein gene (pDec2-EGFP) was delivered to mouse skin using the gene gun, expression of the corresponding gene product was observed in the epidermal compartment almost exclusively by the IA+ population (ie LC). LC in the gene gun-treated sites showed features of mature DC and they migrated to the draining lymph node, suggesting that LC-targeted gene expression may lead to the development of immune responses. In fact, EGFP-specific cellular immune responses became detectable after gene gun-mediated delivery of pDec2-EGFP plasmid. These results introduce a new concept that LC function can be genetically manipulated in situ by the combination of gene gun-mediated DNA delivery and a DC-specific promoter.

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Acknowledgements

We thank Lesa Ellinger and Dale Edelbaum for technical assistance and Pat Adcock for secretarial assistance. This study was supported by NIH grants (RO1-AR35068, RO1-AR43777, and RO1-AI43262) and by CERIES Award (AT).

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Morita, A., Ariizumi, K., Ritter III, R. et al. Development of a Langerhans cell-targeted gene therapy format using a dendritic cell-specific promoter. Gene Ther 8, 1729–1737 (2001). https://doi.org/10.1038/sj.gt.3301580

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