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Gene therapy to target dendritic cells from blood to lymph nodes

Gene Therapy volume 10, pages 1479–1486 (2003)Cite this article

Abstract

Peripheral lymph nodes (PLN) are strategic microenvironments where antigen-presenting dendritic cells (DC), loaded with environmental antigens, and naive lymphocytes meet to initiate immune responses. The unique capacity of DC to induce primary immune responses has led to their use in clinical medicine; however, delivering DC to lymph nodes is problematic. Intravenously injected DC cannot access to PLN, while DC injected into tissue migrate inefficiently through lymphatics to PLN. We achieved DC targeting to T-cell areas of PLN by endowing DC with a novel receptor for peripheral node addressin (PNAd), an adhesion molecule present on the lymph node venular endothelium. This novel receptor is a chimeric E/L-selectin (ELS) that, we have previously shown, binds to PNAd. DC were genetically modified by retroviral transduction to express ELS. ELS expression was targeted to tips of microvilli, and mediated rolling of DC on PNAd both in vivo and in vitro. Such genetically engineered DC could extravasate directly from blood through the lymph node endothelium as opposed to nontransduced DC. This study provides evidence that the trafficking of DC can be modified using gene transfer technologies. More efficient delivery of DC to PLN should assist the development of improved vaccination strategies.

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Acknowledgements

Caroline Robert was supported by a Dermatology Foundation fellowship. This work was supported by National Institutes of Health grants R01 HL54936, R01 HL62524, P01 HL 56949 (to UH von Andrian) and R37 AI25082, R01 AI41707, R01 AR40124, P30 AR42689 (to TS Kupper). Christoph Klein was initially supported by the Deutsche Forschungsgemeinschaft and is a Scholar of the American Society of Hematology.

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Author notes

  1. C Robert

    Present address: Department of Dermatology, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94 801, Villejuif, France

  2. C Klein

    Present address: Department of Pediatric Hematology/Oncology, Medical School Hannover, Carl Neuberg Strasse 1, 30625, Hannover, Germany

  3. C Robert and C Klein: The first two authors, contributed equally to the work

Authors and Affiliations

  1. Department of Dermatology, Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, MA, USA

    C Robert & T S Kupper

  2. Department of Genetics, Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Boston, MA, USA

    C Klein & R C Mulligan

  3. Department of Pathology, Center for Blood Research, Harvard Medical School, Boston, MA, USA

    G Cheng, A Kogan & U H von Andrian

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  1. C Robert
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  2. C Klein
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  3. G Cheng
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  6. U H von Andrian
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  7. T S Kupper
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Robert, C., Klein, C., Cheng, G. et al. Gene therapy to target dendritic cells from blood to lymph nodes. Gene Ther 10, 1479–1486 (2003). https://doi.org/10.1038/sj.gt.3302008

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  • DOI: https://doi.org/10.1038/sj.gt.3302008

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