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

Sapienza University of Rome, Roma, Latium, Italy
Gene Therapy (Impact Factor: 3.1). 04/2007; 14(6):533-44. DOI: 10.1038/
Source: PubMed


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)-alpha play an essential role in both the acute phase and antibody response against Ad, respectively. As TNF-alpha controls the immune response and the development of the immune system, we examined here the consequence of blockade of TNF-alpha 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 beta-galactosidase or alpha1-antitrypsin transgene in wild-type (IL-6(+/+)) but also in IL-6-deficient mice (IL-6(-/-)) to analyze how TNF-alpha and IL-6 diminish liver gene transfer efficacy. Blockade of TNF-alpha 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-alpha drug, confirmed the importance of controlling proinflammatory cytokines during gene therapy by adenoviral vectors.

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    • "This study also confirmed that the efficacy of TNFR1-IgG was similar to that of the anti-TNFα drug, Etanercept®, (human TNFR type 2 fused to human Fc region of immunoglobulin) [55]. However, treatments with TNFα blockers were continued for extended periods of time after Ad injection (for at least 24 days) [55], and may predispose to a more global immune suppression. Finally, IP injection of an Erk inhibitor (U0126), 160 mg/kg, 30 minutes prior and six hours post-Ad injection, was able to reduce some aspects of Ad-triggered inflammatory responses, including reduced activation of IP-10 [56]. "
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