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Tumor necrosis factor alpha plays a central role in immune-mediated clearance of adenoviral vectors.

TitleTumor necrosis factor alpha plays a central role in immune-mediated clearance of adenoviral vectors.
Publication TypeJournal Article
Year of Publication1997
AuthorsElkon KB, Liu CC, Gall JG, Trevejo J, Marino MW, Abrahamsen KA, Song X, Zhou JL, Old LJ, Crystal RG, Falck-Pedersen E
JournalProc Natl Acad Sci U S A
Volume94
Issue18
Pagination9814-9
Date Published1997 Sep 02
ISSN0027-8424
KeywordsAdenoviridae, Animals, Cell Line, Gene Transfer Techniques, Genetic Vectors, Immunity, Mice, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha
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 alpha (TNF-alpha)] 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-alpha > Fas > perforin. TNF-alpha did not have a curative effect on infected hepatocytes, as the administration of TNF-alpha to infected severe combined immunodeficient mice or to infected cultures in vitro had no specific effect on virus persistence. However, TNF-alpha-deficient mice demonstrated a striking reduction in the leukocytic infiltration early on in the infection, suggesting that TNF-alpha 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-alpha in elimination of Ad gene transfer vectors. This result is particularly important because viral proteins that disable TNF-alpha function have been removed from most Ad vectors, rendering them highly susceptible to TNF-alpha-mediated elimination.

DOI10.1073/pnas.94.18.9814
Alternate JournalProc Natl Acad Sci U S A
PubMed ID9275208
PubMed Central IDPMC23274
Grant ListP01 HL051746 / HL / NHLBI NIH HHS / United States
P01 HL51746 / HL / NHLBI NIH HHS / United States
SLE P50-AR42588 / AR / NIAMS NIH HHS / United States

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