The immunogenicity of recombinant adenoviruses (Ad) constitutes a major concern for their use in gene therapy. Antibody- and cell-mediated immune responses triggered by adenoviral vectors hamper long-term transgene expression and efficient viral readministration. We previously reported that interleukin (IL)-6 and tumor necrosis factor (TNF)-a play an essential role in both the acute phase and antibody response against Ad, respectively. As TNF-a controls the immune response and the development of the immune system, we examined here the consequence of blockade of TNF-a activity through Ad-mediated gene delivery of a dimeric mouse TNFR1-IgG fusion protein on transgene expression from a second Ad. Ad encoding TNFR1-IgG (AdTNFR1-Ig) was injected intravenously along with Ad encoding b-galactosidase or a1-antitrypsin transgene in wild-type (IL-6+/+) but also in IL-6-deficient mice (IL-6/) to analyze how TNF-a and IL-6 diminish liver gene transfer efficacy. Blockade of TNF-a leads to increased transgene expression in both wild-type and IL-6/ mice due to a reduced inflammatory response and to diminished recruitment of macrophages and NK cells towards the liver. Antibody responses against adenoviral particles and expressed transgenes were only delayed in AdTNFR1- Ig-treated wild-type mice, but were markedly reduced in AdTNFR1-Ig-treated IL-6/ mice. Finally, treatment of mice with etanercept, a clinically approved anti-TNF-a drug, confirmed the importance of controlling proinflammatory cytokines during gene therapy by adenoviral vectors

Respective roles of TNF-alpha and IL-6 in the immune response-elicited by adenovirus-mediated gene transfer in mice / K., Benihoud; S., Esselin; D., Descamps; B., Jullienne; Salone, Barbara; P., Bobé; D., Bonardelle; E., Connault; P., Opolon; Saggio, Isabella; M., Perricaudet. - In: GENE THERAPY. - ISSN 0969-7128. - STAMPA. - 14:6(2007), pp. 533-544. [10.1038/sj.gt.3302885]

Respective roles of TNF-alpha and IL-6 in the immune response-elicited by adenovirus-mediated gene transfer in mice.

SALONE, Barbara;SAGGIO, Isabella;
2007

Abstract

The immunogenicity of recombinant adenoviruses (Ad) constitutes a major concern for their use in gene therapy. Antibody- and cell-mediated immune responses triggered by adenoviral vectors hamper long-term transgene expression and efficient viral readministration. We previously reported that interleukin (IL)-6 and tumor necrosis factor (TNF)-a play an essential role in both the acute phase and antibody response against Ad, respectively. As TNF-a controls the immune response and the development of the immune system, we examined here the consequence of blockade of TNF-a activity through Ad-mediated gene delivery of a dimeric mouse TNFR1-IgG fusion protein on transgene expression from a second Ad. Ad encoding TNFR1-IgG (AdTNFR1-Ig) was injected intravenously along with Ad encoding b-galactosidase or a1-antitrypsin transgene in wild-type (IL-6+/+) but also in IL-6-deficient mice (IL-6/) to analyze how TNF-a and IL-6 diminish liver gene transfer efficacy. Blockade of TNF-a leads to increased transgene expression in both wild-type and IL-6/ mice due to a reduced inflammatory response and to diminished recruitment of macrophages and NK cells towards the liver. Antibody responses against adenoviral particles and expressed transgenes were only delayed in AdTNFR1- Ig-treated wild-type mice, but were markedly reduced in AdTNFR1-Ig-treated IL-6/ mice. Finally, treatment of mice with etanercept, a clinically approved anti-TNF-a drug, confirmed the importance of controlling proinflammatory cytokines during gene therapy by adenoviral vectors
2007
TNF-a, IL-6, immune response; gene therapy
01 Pubblicazione su rivista::01a Articolo in rivista
Respective roles of TNF-alpha and IL-6 in the immune response-elicited by adenovirus-mediated gene transfer in mice / K., Benihoud; S., Esselin; D., Descamps; B., Jullienne; Salone, Barbara; P., Bobé; D., Bonardelle; E., Connault; P., Opolon; Saggio, Isabella; M., Perricaudet. - In: GENE THERAPY. - ISSN 0969-7128. - STAMPA. - 14:6(2007), pp. 533-544. [10.1038/sj.gt.3302885]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/411084
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