Tumor necrosis factor α plays a central role in immune-mediated clearance of adenoviral vectors Journal Article
| Authors: | Elkon, K. B.; Liu, C. C.; Gall, J. G.; Trevejo, J.; Marino, M. W.; Abrahamsen, K. A.; Song, X.; Zhou, J. L.; Old, L. J.; Crystal, R. G.; Falck-Pedersen, E. |
| Article Title: | Tumor necrosis factor α plays a central role in immune-mediated clearance of adenoviral vectors |
| Abstract: | Adenovirus (Ad) gene transfer vectors are rapidly cleared from infected hepatocytes in mice. To determine which effector mechanisms are responsible for elimination of the Ad vectors, we infected mice that were genetically compromised in immune effector pathways [perforin, Fas, or tumor necrosis factor α (TNF-α)] with the Ad vector, Ad5-chloramphenicol acetyl transferase (CAT). Mice were sacrificed at 7-60 days postinfection, and the levels of CAT expression in the liver determined by a quantitative enzymatic assay. When the livers of infected mice were harvested 28 days postinfection, the levels of CAT expression revealed that the effectors most important for the elimination of the Ad vector were TNF-α > Fas > perforin. TNF-α did not have a curative effect on infected hepatocytes, as the administration of TNF- α to infected severe combined immunodeficient mice or to infected cultures in vitro had no specific effect on virus persistence. However, TNF-α- deficient mice demonstrated a striking reduction in the leukocytic infiltration early on in the infection, suggesting that TNF-α deficiency resulted in impaired recruitment of inflammatory cells to the site of inflammation. In addition, the TNF-deficient mice had a significantly reduced humoral immune response to virus infection. These results demonstrate a dominant role of TNF-α in elimination of Ad gene transfer vectors. This result is particularly important because viral proteins that disable TNF-α function have been removed from most Ad vectors, rendering them highly susceptible to TNF-α-mediated elimination. |
| Keywords: | controlled study; nonhuman; animal cell; mouse; animals; mice; animal tissue; cell infiltration; fas antigen; cell line; animal experiment; mice, inbred c57bl; animalia; genetic vectors; tumor necrosis factor alpha; tumor necrosis factor-alpha; perforin; virus infection; immunity; liver cell; humoral immunity; adenoviridae; virus vector; gene transfer techniques; adenovirus; alphavirus; felis catus; priority journal; article; chloramphenicol acetyltransferase; liver clearance |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 94 |
| Issue: | 18 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 1997-09-02 |
| Start Page: | 9814 |
| End Page: | 9819 |
| Language: | English |
| DOI: | 10.1073/pnas.94.18.9814 |
| PUBMED: | 9275208 |
| PROVIDER: | scopus |
| PMCID: | PMC23274 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 17 March 2017 -- Source: Scopus |
Altmetric
Citation Impact
Related MSK Work