Inhibition of Tumor Necrosis FactorαDecreases Inflammation and Prolongs Adenovirus Gene Expression in Lung and Liver

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Abstract
The clinical application of adenoviral gene therapy currently is impeded by the potent host immune response to the virus, which limits the duration of its effects. In these studies, we investigated the role of TNF-α and of a soluble TNF receptor (TNF-bp) in the inflammatory response and expression of a lacZ-expressing adenovirus (AdCMVlacZ) in the liver and lung of mice. The expression of the recombinant adenovirus was studied in mouse liver and lung by determining the activity of the lacZ gene product of the adenovirus. The mononuclear cell inflammatory response was determined histologically at different times after intravenous or intranasal administration of AdCMVlacZ. The cytotoxic T cell and antibody response to the adenovirus was determined. Treatment with TNF-bp reduced circulating levels of TNF-α, greatly reduced the inflammatory response, and resulted in prolonged expression of lacZ for up to 30 days in the liver and lung after either intravenous or intranasal administration of adenovirus. Treatment with TNF-bp had no effect on anti-adenovirus antibodies and induction of cytotoxic T cells 30 days after administration of AdCMVlacZ. These results indicate that TNF-α is the primary factor driving the early inflammatory response leading to elimination of adenovirus-infected cells in the liver and lung and that TNF-bp is capable of inhibiting these effects. We examined the effectiveness of neutralization of TNF-α with a soluble TNF receptor type I (sTNF-RI) in the inhibition of inflammation and prolongation of lacZ expression after AdCMVlacZ gene therapy. sTNF-RI reduced serum TNF-α to undetectable levels after adenovirus administration, decreased liver and pulmonary inflammatory response, and enhanced expression of the lacZ gene. These results indicate that treatment with the novel sTNF-RI during gene therapy administration may be efficacious in minimizing the inflammatory response and increasing gene therapy efficacy.

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