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

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 vector