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题名:Respective roles of TNF-α and IL-6 in the immune response-elicited by adenovirus-mediated gene transfer in mice
作者:K Benihoud, S Esselin, D Descamps,...
来源:Gene Therapy (16 Nov 2006) Original Article
URL :http://dx.doi.org/10.1038/sj.gt.3302885
日期:061215
摘要:K Benihoud1,2, S Esselin1, D Descamps1, B Jullienne1, B Salone3, P Bobé2,4, D Bonardelle4, E Connault1, P Opolon1, I Saggio3 and M Perricaudet1

1Univ Paris-Sud, Faculté des Sciences, Orsay Cedex, France
2CNRS UMR 8121, Institut Gustave Roussy, Villejuif Cedex, France
3Department of Genetics and Molecular Biology, University of Rome La Sapienza, Rome, Italy
4CNRS UPR 9045, Villejuif Cedex, France

Correspondence: Dr K Benihoud, Vectorologie et Transfert de Gènes UMR 8121 CNRS/Université Paris XI/IGR, Institut Gustave Roussy PR2, 39, rue Camille Desmoulins 94805, Villejuif Cedex, France. E-mail: benihoud@igr.fr


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)- play an essential role in both the acute phase and antibody response against Ad, respectively. As TNF- controls the immune response and the development of the immune system, we examined here the consequence of blockade of TNF- 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 -galactosidase or 1-antitrypsin transgene in wild-type (IL-6+/+) but also in IL-6-deficient mice (IL-6-/-) to analyze how TNF- and IL-6 diminish liver gene transfer efficacy. Blockade of TNF- 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- drug, confirmed the importance of controlling proinflammatory cytokines during gene therapy by adenoviral vectors.

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