Inhibition of tumor necrosis factor alpha by an adenovirus-encoded soluble fusion protein extends transgene expression in the liver and lung.
| Publication Type | Academic Article |
| Authors | Peng Y, Trevejo J, Zhou J, Marino M, Crystal R, Falck-Pedersen E, Elkon K |
| Journal | J Virol |
| Volume | 73 |
| Issue | 6 |
| Pagination | 5098-109 |
| Date Published | 06/01/1999 |
| ISSN | 0022-538X |
| Keywords | Adenoviridae, Liver, Lung, 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. |
| DOI | 10.1128/JVI.73.6.5098-5109.1999 |
| PubMed ID | 10233973 |
| PubMed Central ID | PMC112555 |