title: Gene Therapy against Murine Melanoma B16F10-Nex2 Using IL-13Ralpha2-Fc Chimera and Interleukin 12 in Association with a Cyclopalladated Drug.
abstract: Interleukin 13 (IL-13) is immunoregulatory in many diseases, including cancer. The protective or suppressive role of CD1-restricted natural killer T cells (NKT cells) in tumor immunosurveillance and immunity is well documented. Interleukin 12 (IL-12) can activate type I NKT cells to produce interferon-gamma (IFN-gamma), whereas type II NKT cells may produce IL-13. The high-affinity chain of IL-13Ralpha2 may act as negative inhibitor, suppressing the action of IL-13 and helping to maintain tumor immunosurveillance. We constructed an mIL-13Ralpha2-Fc chimera in a eukaryotic expression vector and confirmed the identity of the recombinant protein by immunoblot analysis and binding to IL-13 in chemiluminescent ELISA. Such DNA vaccine was tested against syngeneic B16F10-Nex2 murine melanoma. In vivo experiments showed a protective effect mediated by high production of IFN-gamma and down-regulation of anti-inflammatory interleukins mainly by NKT 1.1(+) T cells. Biochemoterapy in vivo with plasmid encoding mIL-13Ralpha2-Fc in association with plasmid encoding IL-12 and the 7A cyclopalladated drug led to a significant reduction in the tumor evolution with 30% tumor-free mice. We conclude that IL-12 gene therapy, followed by continuous administration of IL-13Ralpha2-Fc gene along with 7A-drug has antitumor activity involving the high production of proinflammatory cytokines and low immune suppression, specifically by NK1.1(+)T cells producing IL-13 and IL-10.
authors.affiliation: Unidade de Oncologia Experimental (UNONEX), Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: Flavia
authors.initials: F
authors.lastname: Hebeler-Barbosa
authors.forename: Elaine G
authors.initials: EG
authors.lastname: Rodrigues
authors.forename: Rosana
authors.initials: R
authors.lastname: Puccia
authors.forename: Antonio Cf
authors.initials: AC
authors.lastname: Caires
authors.forename: Luiz R
authors.initials: LR
authors.lastname: Travassos
references.citation: Int J Cancer. 2003 Nov 10;107(3):498-504
references.pmid: 14506753
references.citation: Cancer Res. 2005 Dec 15;65(24):11743-51
references.pmid: 16357187
references.citation: Nat Immunol. 2000 Dec;1(6):515-20
references.pmid: 11101874
references.citation: J Immunol. 2003 Feb 1;170(3):1197-201
references.pmid: 12538676
references.citation: J Immunol. 1998 Sep 1;161(5):2317-24
references.pmid: 9725226
references.citation: Immunity. 1998 Feb;8(2):255-64
references.pmid: 9492006
references.citation: J Immunol. 2000 Feb 1;164(3):1458-62
references.pmid: 10640762
references.citation: Nat Med. 2003 May;9(5):582-8
references.pmid: 12669034
references.citation: Nat Rev Immunol. 2003 Feb;3(2):133-46
references.pmid: 12563297
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13020-5
references.pmid: 12232042
references.citation: J Immunol. 1999 Jan 15;162(2):920-30
references.pmid: 9916716
references.citation: J Immunol. 1994 Feb 1;152(3):1094-102
references.pmid: 7507958
references.citation: Cancer Res. 1975 Jan;35(1):218-24
references.pmid: 1109790
references.citation: Mol Ther. 2002 Jun;5(6):668-75
references.pmid: 12027550
references.citation: Int J Cancer. 2005 Mar 10;114(1):80-7
references.pmid: 15523692
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):586-90
references.pmid: 14699044
references.citation: J Exp Med. 1998 Jul 20;188(2):287-96
references.pmid: 9670041
references.citation: J Exp Med. 2005 Dec 19;202(12):1627-33
references.pmid: 16365146
references.citation: Nat Med. 2006 Jan;12(1):99-106
references.pmid: 16327802
references.citation: Cytokines Cell Mol Ther. 2002;7(3):107-16
references.pmid: 12850810
references.citation: Nature. 1993 Mar 18;362(6417):248-50
references.pmid: 8096327
references.citation: Science. 1998 Dec 18;282(5397):2261-3
references.pmid: 9856950
references.citation: J Exp Med. 2000 Feb 21;191(4):661-8
references.pmid: 10684858
references.citation: J Biol Chem. 1996 Nov 15;271(46):29265-70
references.pmid: 8910586
references.citation: J Exp Med. 2005 Nov 7;202(9):1279-88
references.pmid: 16275765
references.citation: J Exp Med. 2002 Mar 4;195(5):625-36
references.pmid: 11877485
references.citation: Science. 1998 Dec 18;282(5397):2258-61
references.pmid: 9856949
references.citation: J Exp Med. 2002 Mar 4;195(5):637-41
references.pmid: 11877486
references.citation: Hybridoma. 1996 Dec;15(6):415-22
references.pmid: 8985752
references.citation: J Immunol. 2004 Jun 15;172(12):7368-76
references.pmid: 15187113
references.citation: J Exp Med. 1993 Oct 1;178(4):1223-30
references.pmid: 8104230
references.citation: Science. 1997 Nov 28;278(5343):1623-6
references.pmid: 9374462
references.citation: Trends Immunol. 2007 Nov;28(11):491-6
references.pmid: 17964217
references.citation: Int Immunol. 2004 Jul;16(7):1009-17
references.pmid: 15184346
references.citation: Immunol Today. 1994 Jan;15(1):19-26
references.pmid: 7907877
references.citation: J Immunol. 1996 May 1;156(9):3366-73
references.pmid: 8617962
references.citation: Cancer Res. 2006 Apr 1;66(7):3869-75
references.pmid: 16585215
references.citation: J Immunol. 1999 Sep 1;163(5):2387-91
references.pmid: 10452972
references.citation: Microbiology (Reading). 2002 Aug;148(Pt 8):2607-2615
references.pmid: 12177355
references.citation: J Exp Med. 1982 Jun 1;155(6):1823-41
references.pmid: 6176669
references.citation: Nat Med. 2006 Jan;12(1):13-4
references.pmid: 16397542
references.citation: Annu Rev Immunol. 2003;21:425-56
references.pmid: 12615888
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6291-6
references.pmid: 8692808
references.citation: J Immunol. 1999 Jan 1;162(1):78-87
references.pmid: 9886372
references.citation: Immunol Today. 1996 Mar;17(3):108-10
references.pmid: 8820266
references.citation: J Clin Invest. 2007 Nov;117(11):3169-72
references.pmid: 17975660
references.citation: J Immunol. 2000 Sep 1;165(5):2665-70
references.pmid: 10946296
references.citation: Cancer Immunol Immunother. 2008 Jun;57(6):907-12
references.pmid: 18004566
references.citation: Proc Natl Acad Sci U S A. 1993 May 15;90(10):4455-9
references.pmid: 8506285
references.citation: J Immunol. 2007 Oct 15;179(8):5126-36
references.pmid: 17911598
references.citation: Nat Rev Immunol. 2004 Mar;4(3):231-7
references.pmid: 15039760
references.citation: Blood. 2002 Feb 15;99(4):1259-66
references.pmid: 11830474
references.citation: Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):497-501
references.pmid: 8552669
references.citation: Cancer Res. 2003 Jun 15;63(12):3058-60
references.pmid: 12810627
references.citation: J Exp Med. 1999 Apr 5;189(7):1121-8
references.pmid: 10190903
references.citation: J Immunol. 1992 Aug 15;149(4):1211-5
references.pmid: 1386860
references.citation: J Immunol. 1995 Jan 15;154(2):799-803
references.pmid: 7529288
references.citation: J Exp Med. 2003 Dec 1;198(11):1741-52
references.pmid: 14657224
references.citation: J Immunol. 2002 Nov 15;169(10):5796-804
references.pmid: 12421960
references.citation: Annu Rev Immunol. 1989;7:145-73
references.pmid: 2523712
references.citation: J Allergy Clin Immunol. 2003 Apr;111(4):720-8
references.pmid: 12704349
references.citation: Cytokine Growth Factor Rev. 2002 Apr;13(2):155-68
references.pmid: 11900991
references.citation: Blood. 2001 May 1;97(9):2673-9
references.pmid: 11313257
references.citation: Nat Rev Immunol. 2003 Aug;3(8):630-41
references.pmid: 12974478
references.citation: J Exp Med. 2002 Jul 1;196(1):119-27
references.pmid: 12093876