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

doi:10.1038/sj.gt.3301872

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 journal › Article › peer-review

24 Scopus citations

Abstract

C57BL/10 (B10; 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 naïve allogeneic C3H/HeJ (C3H; H2^k) 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 language	English (US)
Pages (from-to)	143-152
Number of pages	10
Journal	Gene therapy
Volume	10
Issue number	2
DOIs	https://doi.org/10.1038/sj.gt.3301872
State	Published - Jan 2003
Externally published	Yes

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

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 na{\"i}ve allogeneic C3H/HeJ (C3H; H2k) T-cells. Compared with Ad-Neo DC, Ad-IL-4 DC were also more effective in priming na{\"i}ve 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.",

keywords = "Dendritic cells, Gene therapy, Transplantation",

author = "K. Kaneko and Z. Wang and Kim, {S. H.} and Morelli, {A. E.} and Robbins, {P. D.} and Thomson, {A. W.}",

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)",

year = "2003",

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doi = "10.1038/sj.gt.3301872",

language = "English (US)",

volume = "10",

pages = "143--152",

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T1 - Dendritic cells genetically engineered to express IL-4 exhibit enhanced IL-12p70 production in response to CD40 ligation and accelerate organ allograft rejection

AU - Kaneko, K.

AU - Wang, Z.

AU - Kim, S. H.

AU - Morelli, A. E.

AU - Robbins, P. D.

AU - Thomson, A. W.

N1 - 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)

PY - 2003/1

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Keywords

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