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 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 (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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References
Steinman RM . The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991; 9: 271–296.
Banchereau J, Steinman RM . Dendritic cells and the control of immunity. Nature 1998; 392: 245–252.
Larsen CP, Morris PJ, Austyn JM . Migration of dendritic leukocytes from cardiac allografts into host spleens. A novel pathway for initiation of rejection. J Exp Med 1990; 171: 307–314.
Lechler RI, Batchelor JR . Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells. J Exp Med 1982; 155: 31–41.
Lu L et al. Bone marrow-derived dendritic cell progenitors (NLDC 145+, MHC class II+, B7-1dim, B7-2-) induce alloantigen-specific hyporesponsiveness in murine T lymphocytes. Transplantation 1995; 60: 1539–1545.
Fu F et al. Costimulatory molecule-deficient dendritic cell progenitors (MHC class II+, CD80dim, CD86-) prolong cardiac allograft survival in nonimmunosuppressed recipients. Transplantation 1996; 62: 659–665.
Rastellini C et al. Granulocyte/macrophage colony-stimulating factor-stimulated hepatic dendritic cell progenitors prolong pancreatic islet allograft survival. Transplantation 1995; 60: 1366–1370.
Lutz MB et al. Immature dendritic cells generated with low doses of GM-CSF in the absence of IL-4 are maturation resistant and prolong allograft survival in vivo. Eur J Immunol 2000; 30: 1813–1822.
Jonuleit H et al. Induction of interleukin 10-producing, nonproliferating CD4(+) T-cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 2000; 192: 1213–1222.
Dhodapkar MV et al. Antigen-specific inhibition of effector T-cell function in humans after injection of immature dendritic cells. J Exp Med 2001; 193: 233–238.
Hackstein H, Morelli AE, Thomson AW . Designer dendritic cells for tolerance induction: guided not misguided missiles. Trends Immunol 2001; 22: 437–442.
Morelli AE, Hackstein H, Thomson AW . Potential of tolerogenic dendritic cells for transplantation. Semin Immunol 2001; 13: 323–335.
Lu L et al. Genetic engineering of dendritic cells to express immunosuppressive molecules (viral IL-10, TGF-beta, and CTLA4Ig). J Leukoc Biol 1999; 66: 293–296.
Takayama T, Tahara H, Thomson AW . Transduction of dendritic cell progenitors with a retroviral vector encoding viral interleukin-10 and enhanced green fluorescent protein allows purification of potentially tolerogenic antigen-presenting cells. Transplantation 1999; 68: 1903–1909.
Gorczynski RM et al. Synergy in induction of increased renal allograft survival after portal vein infusion of dendritic cells transduced to express TGFbeta and IL-10, along with administration of CHO cells expressing the regulatory molecule OX-2. Clin Immunol 2000; 95: 182–189.
Lu L et al. Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients. Gene Ther 1999; 6: 554–563.
Takayama T et al. Feasibility of CTLA4Ig gene delivery and expression in vivo using retrovirally transduced myeloid dendritic cells that induce alloantigen-specific T-cell anergy in vitro. Gene Ther 2000; 7: 1265–1273.
Matsue H et al. Induction of antigen-specific immunosuppression by CD95L cDNA-transfected ‘killer’ dendritic cells. Nat Med 1999; 5: 930–937.
Min WP et al. Dendritic cells genetically engineered to express Fas ligand induce donor-specific hyporesponsiveness and prolong allograft survival. J Immunol 2000; 164: 161–167.
Lee WC et al. Phenotype, function, and in vivo migration and survival of allogeneic dendritic cell progenitors genetically engineered to express TGF-beta. Transplantation 1998; 66: 1810–1817.
Coates PT 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 2001; 8: 1224–1233.
O'Rourke RW et al. A dendritic cell line genetically modified to express CTLA4-IG as a means to prolong islet allograft survival. Transplantation 2000; 69: 1440–1446.
Chomarat P, Rybak ME, Banchereau J . Interleukin-4 In: Thomson AW (ed) The Cytokine Handbook. Academic Press: San Diego, 1998, pp 133–174.
Levy AE, Alexander JW . Administration of intragraft interleukin-4 prolongs cardiac allograft survival in rats treated with donor-specific transfusion/cyclosporine. Transplantation 1995; 60: 405–406.
He XY et al. Treatment with interleukin-4 prolongs allogeneic neonatal heart graft survival by inducing T helper 2 responses. Transplantation 1998; 65: 1145–1152.
Rabinovitch A et al. Combination therapy with cyclosporine and interleukin-4 or interleukin-10 prolongs survival of synergeneic pancreatic islet grafts in nonobese diabetic mice: islet graft survival does not correlate with mRNA levels of type 1 or type 2 cytokines, or transforming growth factor-beta in the islet grafts. Transplantation 1997; 64: 1525–1531.
Takeuchi T et al. Murine interleukin 4 transgenic heart allograft survival prolonged with down-regulation of the Th1 cytokine mRNA in grafts. Transplantation 1997; 64: 152–157.
Kato H et al. Adenovirus-mediated gene transfer of IL-4 prolongs rat renal allograft survival and inhibits the p21(ras)-activation pathway. Transplant Proc 2000; 32: 245–246.
Fanslow WC et al. Regulation of alloreactivity in vivo by IL-4 and the soluble IL-4 receptor. J Immunol 1991; 147: 535–540.
Raisanen-Sokolowski A, et al. Heart transplants in interferon-gamma, interleukin 4, and interleukin 10 knockout mice. Recipient environment alters graft rejection. J Clin Invest 1997; 100: 2449–2456.
Kim SH et al. Effective treatment of established murine collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express IL-4. J Immunol 2001; 166: 3499–3505.
Morita Y et al. Dendritic cells genetically engineered to express IL-4 inhibit murine collagen-induced arthritis. J Clin Invest 2001; 107: 1275–1284.
Morelli AE et al. Recombinant adenovirus induces maturation of dendritic cells via an NF-kappaB-dependent pathway. J Virol 2000; 74: 9617–9628.
Niimi M et al. Operational tolerance induced by pretreatment with donor dendritic cells under blockade of CD40 pathway. Transplantation 2001; 72: 1556–1562.
Lu L et al. Blockade of the CD40–CD40 ligand pathway potentiates the capacity of donor-derived dendritic cell progenitors to induce long-term cardiac allograft survival. Transplantation 1997; 64: 1808–1815.
David A et al. Interleukin-10 produced by recombinant adenovirus prolongs survival of cardiac allografts in rats. Gene Ther 2000; 7: 505–510.
Gross A, Ben-Sasson SZ, Paul WE . Anti-IL-4 diminishes in vivo priming for antigen-specific IL-4 production by T-cells. J Immunol 1993; 150: 2112–2120.
Abehsira-Amar O et al. IL-4 plays a dominant role in the differential development of Th0 into Th1 and Th2 cells. J Immunol 1992; 148: 3820–3829.
Hochrein H et al. Interleukin (IL)-4 is a major regulatory cytokine governing bioactive IL-12 production by mouse and human dendritic cells. J Exp Med 2000; 192: 823–833.
Kalinski P et al. IL-4 is a mediator of IL-12p70 induction by human Th2 cells: reversal of polarized Th2 phenotype by dendritic cells. J Immunol 2000; 165: 1877–1881.
Bullens DM et al. CD40L-induced IL-12 production is further enhanced by the Th2 cytokines IL-4 and IL-13. Scand J Immunol 2001; 53: 455–463.
Schulz O et al. CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity 2000; 13: 453–462.
Lee WC et al. Contrasting effects of myeloid dendritic cells transduced with an adenoviral vector encoding interleukin-10 on organ allograft and tumour rejection. Immunology 2000; 101: 233–241.
Oriss TB et al. Evidence of positive cross-regulation on Th1 by Th2 and antigen-presenting cells: effects on Th1 induced by IL-4 and IL-12. J Immunol 1999; 162: 1999–2007.
Inaba K et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 1992; 176: 1693–1702.
Hardy S et al. Construction of adenovirus vectors through Cre-lox recombination. J Virol 1997; 71: 1842–1849.
Ono K, Lindsey ES . Improved technique of heart transplantation in rats. J Thorac Cardiovasc Surg 1969; 7: 225–229.
Acknowledgements
We acknowledge Ms Shelly L Shaplye for her skilled assistance in manuscript preparation and Ms Alison J Logar for her expert assistance with flow cytometry.
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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)
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Kaneko, K., Wang, Z., Kim, S. et al. Dendritic cells genetically engineered to express IL-4 exhibit enhanced IL-12p70 production in response to CD40 ligation and accelerate organ allograft rejection. Gene Ther 10, 143–152 (2003). https://doi.org/10.1038/sj.gt.3301872
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DOI: https://doi.org/10.1038/sj.gt.3301872
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