Circulation, Vol 89, 846-851, Copyright © 1994 by American Heart Association
T Yamada, A Matsumori and S Sasayama
BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) has been reported to
have an antiviral effect in vitro; however, its in vivo effect remains to
be clarified. METHODS AND RESULTS: To investigate the role of TNF-alpha in
viral myocarditis using a murine model induced by encephalomyocarditis
virus (EMCV), we evaluated (1) plasma TNF-alpha levels by enzyme-linked
immunosorbent assay (ELISA), (2) the effect of recombinant human TNF-alpha
for its possible antiviral effect in vivo, and (3) the effect of
anti-murine TNF-alpha monoclonal antibody (mAb) in vivo. Four-week-old
DBA/2 mice were inoculated intraperitoneally with EMCV (day 0). Mice were
injected intravenously daily with 1 microgram of TNF-alpha or 2 x 10(3)
units of anti-TNF-alpha mAb starting on day -1, day 0, or day 1 until day 2
(TNF-alpha study) or day 4 (anti-TNF-alpha mAb study). A portion of the
mice were killed on day 5 (protocol 1); their hearts were removed, and
plaque assays were performed to demonstrate the myocardial virus content.
The remaining mice were killed on day 14 (protocol 2); myocardial lesions
were examined histopathologically in terms of severity, and their survival
rates were determined. Plasma TNF-alpha concentration was elevated in the
blood of infected mice compared with uninfected mice 3, 5, and 7 days after
virus inoculation. The myocardial virus content was higher in the
TNF-alpha-treated group than in the control group. Histopathological
analysis revealed that myocardial necrosis and cellular infiltration were
more prominent in the TNF-alpha group than in the control group. The
anti-TNF-alpha mAb improved survival and myocardial lesions when its
treatment was started 1 day before virus inoculation. However, it showed no
therapeutic effect when administered simultaneously with the inoculation or
on day 1. CONCLUSIONS: TNF-alpha may play an important role in the very
early stage of the immune response, and anti-TNF-alpha mAb may prevent the
early pathway of acute viral myocarditis.
ARTICLES
Therapeutic effect of anti-tumor necrosis factor-alpha antibody on the murine model of viral myocarditis induced by encephalomyocarditis virus
Department of Internal Medicine, Faculty of Medicine, Kyoto University, Japan.
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