Dendritic cells genetically engineered to express IL-4 exhibit enhanced IL-12p70 production in response to CD40 ligation and accelerate organ allograft rejection

K. Kaneko, Z. Wang, S. H. Kim, A. E. Morelli, P. D. Robbins, A. W. Thomson

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

C57BL/10 (B10; H2b) 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 naïve allogeneic C3H/HeJ (C3H; H2k) T-cells. Compared with Ad-Neo DC, Ad-IL-4 DC were also more effective in priming naïve allogeneic recipients to exhibit specifically enhanced antidonor 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 (IFNγ) 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.

Original languageEnglish (US)
Pages (from-to)143-152
Number of pages10
JournalGene therapy
Volume10
Issue number2
DOIs
StatePublished - Jan 2003
Externally publishedYes

Bibliographical note

Funding Information:
Correspondence: AW Thomson, Department of Surgery, University of Pittsburgh Medical Center, W1544 Biomedical Science Tower, 200 Lothrop St Pittsburgh, PA 15213, USA This work was supported by Public Health Service Grants R01 AI41011 and R01 DK 49745 (to AWT) and R21 HL69725 (to AEM) from the National Institutes of Health, and by the Roche Organ Transplantation Research Foundation (ROTRF 13068349) (to AWT)

Keywords

  • Dendritic cells
  • Gene therapy
  • Transplantation

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