The rationale for use of soluble TNF receptor as a modulator of adenovirus inflammation stems from the observation that TNFa is one of the principal mediators of inflammation after adenovirus gene therapy [41-43]. Neutralization of TNFa with TNFa inhibitors, such as soluble TNFR1 (sTNFRl) greatly reduces tissue injury and cell death after endotoxin and other inflammatory agents. This is a rational approach, since adenovirus takes advantage of TNFa as an immune mediator to promote expression of several immunosubversive proteins supporting its escape from immunosurveil-lance , The interaction of TNFa with its receptor is a strong virulence factor for inflammation and elimination of virus infection. The E3-gpl9 K protein not only prevents CTL recognition of Ad-infected fibroblasts by sequestering
MHC class I proteins in the endoplasmic reticulum, but also E3 proteins 10.4 K, 14.5 K, and 14.7 K function to protect infected cells from TNFa cytolysis. Transgenic mice that express the E3 gene encoding these proteins have been shown to exhibit decreased pulmonary infiltration after intranasal inoculation . Peng et al.  showed that adenovirus gene transfer of an sTNFR results in effective blockade of tumor necrosis factor activity and also prolongs the gene therapy. Therefore, neutralization of TNFa is a rational approach to decrease chronic inflammation as well as prolonged transgene expression.
Certain cytokines such as TNFa can result in rapid clearance of adenovirus or viral therapy. Administration of anti-inflammatory cytokines, such as IL-10, can reduce inflammation and prolong gene therapy , We have evaluated the effect of the treatment with a novel TNF-binding protein (TNF-bp), a polyethylene-glycol (PEG)-linked dimer of sTNFRl, on inflammation of the lung and viral clearance after intranasal administration of AdCMVLacZ (1 x 1010 pfu) [45, 46] (Fig. 3, see color insert). Three days after intranasal administration, there was a moderate inflammatory infiltrate in the lungs of control (CT)-treated C57BL/6-+/4- mice, which peaked at day 7 and was nearly resolved by day 30 (Fig. 3A). In contrast, 3 days after administration of AdCMVLacZ, there was no evidence of an inflammatory infiltrate in the lungs of TNF-bp-treated C57BL/6-+/+ mice and only minimal evidence of infiltration was observed from day 3 through day 30. We next determined the expression of LacZ adenovirus gene-therapy product. The results indicate that the expression of p-galactosidase (¡3-Gal) in control-treated C57BLI6-+/+ mice was high at day 3, but was considerably reduced by day 30 (Fig. 3B). The expression of the (3-Gal in TNF-bp-treated C57BL/6-4-/+ mice was equivalent at day 3 but, in contrast to the control-treated mice, the expression of |3-Gal remained high in the lung through day 30. These results indicate that there is greatly decreased inflammatory disease and prolonged gene expression in AdCMVLacZ-infected mice treated with TNF-bp compared to vehicle-treated mice. The results also indicate that TNFa is a key factor in the pathogenesis of inflammation in AdCMVLacZ-virus-infected mice. Thus, the TNF-bp PEG-linked dimer may be therapeutically useful in reducing the inflammatory response to adenovirus gene therapy.
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