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Title: Gene therapy with interleukin-10 receptor and interleukin-12 induces a protective interferon-gamma-dependent response against B16F10-Nex2 melanoma
Authors: Marchi, L. H. L. [UNIFESP]
Paschoalin, T. [UNIFESP]
Travassos, L. R. [UNIFESP]
Rodrigues, E. G. [UNIFESP]
Universidade Federal de São Paulo (UNIFESP)
Keywords: B16F10-Nex2 melanoma
IL-10 receptor minigene
IL-12 gene
protective response
dendritic cells
Issue Date: 1-Feb-2011
Publisher: Nature Publishing Group
Citation: Cancer Gene Therapy. London: Nature Publishing Group, v. 18, n. 2, p. 110-122, 2011.
Abstract: Antitumor immune responses are associated with proinflammatory cytokines, whereas tumor-developing animals generally have increased the production of immunosuppressive cytokines. Here, we show that splenocytes from C57Bl/6 mice resistant to low doses of B16F10-Nex2 melanoma cells produced twofold or higher interferon-gamma (IFN-gamma)/interleukin-10 (IL-10) ratios, whereas cells from tumor-bearing animals produced predominantly IL-10. IL-10-knockout (IL-10KO) mice were significantly more resistant to B16F10-Nex2 development, producing increased amounts of IL-12 and IFN-gamma. To neutralize IL-10 in vivo, aiming at cancer therapy, recombinant eukaryotic plasmid expressing the soluble extracellular region of the murine IL-10 receptor alpha-chain was constructed (pcDNA3-sIL-10R). Plasmid-treated melanoma-challenged animals showed extended survival time, the protective response was IFN-gamma dependent and enhanced by co-immunization with a plasmid expressing IL-12. Dendritic cells (DCs) from IL-10KO mice, primed with B16F10-Nex2 antigens (TAg), secreted increased amounts of T-helper 1-type cytokines and increased the expression of surface activation markers. Vaccination of C57Bl/6 mice with TAg-activated IL-10KO DCs, as well as with TAg-primed DCs from C57Bl/6 mice transfected with pcDNA3-sIL10R plasmid, significantly increased animal survival. in conclusion, an IFN-gamma-dependent protective response was induced against B16F10-Nex2 cells by neutralization of IL-10 with pcDNA3-sIL10R plasmid. This effect was enhanced by association with IL-12 gene therapy (80% protection), and could be mediated by TAg-primed DCs. Cancer Gene Therapy (2011) 18, 110-122; doi: 10.1038/cgt.2010.58; published online 1 October 2010
ISSN: 0929-1903
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