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Inhibition of tumor necrosis factor alpha by an adenovirus-encoded soluble fusion protein extends transgene expression in the liver and lung.

TitleInhibition of tumor necrosis factor alpha by an adenovirus-encoded soluble fusion protein extends transgene expression in the liver and lung.
Publication TypeJournal Article
Year of Publication1999
AuthorsPeng Y, Trevejo J, Zhou J, Marino MW, Crystal RG, Falck-Pedersen E, Elkon KB
JournalJ Virol
Volume73
Issue6
Pagination5098-109
Date Published1999 Jun
ISSN0022-538X
KeywordsAdenoviridae, Animals, Antibodies, Viral, Antigens, CD, CD8 Antigens, Enzyme-Linked Immunosorbent Assay, fas Receptor, Genetic Therapy, Liver, Lung, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, SCID, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Recombinant Fusion Proteins, Transgenes, Tumor Necrosis Factor-alpha
Abstract

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.

DOI10.1128/JVI.73.6.5098-5109.1999
Alternate JournalJ Virol
PubMed ID10233973
PubMed Central IDPMC112555
Grant ListP01 HL051746 / HL / NHLBI NIH HHS / United States
R01 AR045482 / AR / NIAMS NIH HHS / United States
AR45482 / AR / NIAMS NIH HHS / United States
P01 HL51746 / HL / NHLBI NIH HHS / United States

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