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Journal of Virology, June 1999, p. 5098-5109, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Inhibition of Tumor Necrosis Factor Alpha by an Adenovirus-Encoded Soluble Fusion Protein Extends Transgene Expression in the Liver and Lung

YuFeng Peng,1 Jose Trevejo,2 JunLiang Zhou,1 Michael W. Marino,3 Ronald G. Crystal,4 Erik Falck-Pedersen,2 and Keith B. Elkon1,*

Hospital for Special Surgery, Cornell University Medical Center,1 W. R Hearst Research Foundation Department of Microbiology,2 Department of Medicine, Division of Pulmonary and Critical Care, Weill Medical College of Cornell University/New York Presbyterian Hospital,4 and Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center,3 New York, New York 10021

Received 6 November 1998/Accepted 9 March 1999

The cellular and humoral immune responses to adenovirus (Ad) remain a major barrier to Ad-mediated gene therapy. We recently reported that mice deficient in tumor necrosis factor alpha (TNF-alpha ) or Fas (APO-1, CD95) have prolonged expression of an Ad transgene expressing a foreign protein in the liver. To determine whether blockade of TNF-alpha or Fas would have the same effect in normal mice, we created transgenes that expressed soluble murine CD8 or CD8 fused to the extracellular regions of TNF receptor 1 (TNFR) or Fas and inserted into the left-end region of first-generation (E1/E3-) Ad vectors. Consistent with the results observed in TNF-deficient mice, expression of the TNFR-CD8 fusion protein was prolonged in vivo compared to that of control proteins. Not only did expression of TNFR-CD8 persist in the liver and the lung, but when coadministered with another first-generation vector, the protein provided "transprotection" for the companion vector and transgene. In addition, TNFR-CD8 attenuated the humoral immune response to the Ad. Together, these findings demonstrate that blockade of TNF-alpha is likely to be useful in extending the expression of an Ad-encoded transgene in a gene therapy application.

* Corresponding author. Mailing address: Research Division, Hospital for Special Surgery-Cornell University Medical Center, 535 East 70th St., New York, NY 10021. Phone: (212) 606-1409. Fax: (212) 717-1192. E mail: elkonk{at}hss.edu.

Journal of Virology, June 1999, p. 5098-5109, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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