期刊
GENE THERAPY
卷 10, 期 2, 页码 143-152出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3301872
关键词
dendritic cells; transplantation; gene therapy
类别
资金
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R21HL069725] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI041011] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK049745] Funding Source: NIH RePORTER
- NHLBI NIH HHS [R21 HL 69725] Funding Source: Medline
- NIAID NIH HHS [R01 AI 41011] Funding Source: Medline
- NIDDK NIH HHS [R01 DK 49745] Funding Source: Medline
C57BL/10 (B 10; H2(b)) bone marrow-derived myeloid dendritic cells (DC) propagated in GM-CSF + IL-4 were transduced with r adenoviral (Ad) vectors encoding either control neomycin-resistance gene (Ad-Neo) or murine IL-4 (Ad-IL-4) on day 5 of culture following CD11c immunomagnetic bead purification. Both Ad-Neo- and Ad-IL-4-transduced DC displayed upregulated surface MHC class II and costimulatory molecules (CD40, CD80, CD86). Ad-IL-4 DC secreted higher levels of bioactive IL-12p70 after CD40 ligation or LPS stimulation than either Ad-Neo or unmodified DC. Only Ad-IL-4 DC produced IL-12p70 in primary MLR, in which they induced augmented proliferative responses of naive allogeneic C3H/HeJ (C3H, H2(k)) T-cells. Compared with Ad-Neo DC, Ad-IL-4 DC were also more effective in priming naive allogeneic recipients to exhibit specifically enhanced anti-donor T-cell proliferative and CTL responses. T-cells primed in vivo 7 days previously with Ad-IL-4 DC displayed enhanced secretion of Th2 (IL-4, IL-10) but also higher Th1 cytokine (IFNgamma) production following ex vivo challenge with donor alloAg. Moreover, pretreatment of vascularized heart graft recipients with i.v. Ad-IL-4 DC, 1 week before transplant, significantly accelerated rejection and antagonized the therapeutic effect of anti-CD40L (CD154) mAb. These data contrast markedly with recently reported inhibitory effects of autologous Ad-IL-4 DC on autoimmune inflammatory disease.
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