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

被引:39
作者
Coates, PTH
Krishnan, R
Kireta, S
Johnston, J
Russ, GR
机构
[1] Univ Adelaide, Transplantat Immunol Lab, Woodville, SA 5011, Australia
[2] Univ Adelaide, Dept Med, Woodville, SA 5011, Australia
关键词
interleukin-10; gene therapy; dendritic cells;
D O I
10.1038/sj.gt.3301513
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 x 10(6) 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.
引用
收藏
页码:1224 / 1233
页数:10
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