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Human myeloid dendritic cells transduced with an adenoviral interleukin-10 gene construct inhibit human skin graft rejection in humanized NOD-scid chimeric mice

Gene Therapy volume 8, pages 1224–1233 (2001)Cite this article

Abstract

Human myeloid DC were generated from peripheral blood mononuclear cells by monocyte adhesion and subsequent culture with rhGM-CSF and rhIL-4. We transduced immature (day 5 of culture) myeloid DC with an E1-deleted replication-deficient adenoviral vector encoding the cytokine IL-10 (AdV IL-10) and a control adenovirus MX-17 (AdV MX 17). Human DC transduced with AdV IL-10 showed inhibition of the mixed leukocyte culture, reduced cell surface expression of co-stimulatory molecules (CD80/CD86) and were unable to produce the potent allo-stimulatory cytokine, interleukin-12. In order to test the in vivo properties of these cells a humanized immunodeficient mouse skin transplantation model was developed. Immunodeficient NOD-scid mice were engrafted with human skin, reconstituted via intraperitoneal injection with allogeneic mononuclear cells (MNC) mixed with 1 × 106 DC that were autologous to the skin donor and that had been transduced with either AdV IL-10 or AdV MX-17. Skin grafts were removed at day 7 and 14 after reconstitution and studied histologically for evidence of rejection. In animals that received DC modified with AdV IL-10 there was reduced skin graft rejection as characterized by reduced mononuclear cell infiltration and less dermo–epidermal junction destruction compared with those animals that received DC modified with the control virus alone. Injection of equivalent numbers of donor-derived fibroblasts transduced with AdV IL-10 were ineffective at modifying rejection of skin grafts. Immunosuppressive cytokine gene therapy targeting human DC is a novel means of inhibition of the alloimmune response.

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Acknowledgements

We wish to thank the Australian Red Cross Blood Transfusion Service (Adelaide) for provision of buffy coats. Dr Coates is the recipient of an Australian Government National Health &Medical Research Council Post-Graduate Medical Research Scholarship. The laboratory is supported by grants from the Australian Kidney Foundation.

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Author notes

  1. PTH Coates

    Present address: Department of Surgery, TE Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, 15213, PA, USA

Authors and Affiliations

  1. Transplantation Immunology Laboratory, University of Adelaide, The Queen Elizabeth Hospital Campus, 28 Woodville Rd, Woodville, 5011, South Australia

    PTH Coates, R Krishnan, S Kireta, J Johnston & GR Russ

  2. Department of Medicine, University of Adelaide, The Queen Elizabeth Hospital Campus, 28 Woodville Rd, Woodville, 5011, South Australia

    PTH Coates, R Krishnan & GR Russ

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Coates, P., Krishnan, R., Kireta, S. et al. Human myeloid dendritic cells transduced with an adenoviral interleukin-10 gene construct inhibit human skin graft rejection in humanized NOD-scid chimeric mice. Gene Ther 8, 1224–1233 (2001). https://doi.org/10.1038/sj.gt.3301513

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