Therapeutic effects of FTY720, a new immunosuppressive agent, in a murine model of acute viral myocarditis.
OBJECTIVE
This study examines the efficacy of FTY720 (FTY), a new immunosuppressor, in the treatment of acute viral myocarditis in a murine model.


BACKGROUND
Immunosuppressive agents have no proven therapeutic efficacy in experimental or clinical myocarditis.


METHODS
Encephalomyocarditis virus was inoculated i.p. in DBA/2 mice on day 0. Postinoculation treatment consisted of FTY 10 mg/kg/day p.o. (FTY group), or cyclosporine A (CsA) 40 mg/kg/day p.o. (CsA group) or distilled water p.o. only (control group). Survival until day 14, as well as cardiac histopathology, virus concentrations, cytokines (interleukin [IL]-2, IL-12, interferon [IFN]-gamma and tumor necrosis factor [TNF]-alpha) and nitric oxide (NO) on day 5 were examined.


RESULTS
In the control and CsA groups, all mice died within 10 and 7 days, respectively. However, in the FTY group, 27% of the animals survived up to day 14. Compared with the control group, 1) histological scores were significantly lower in the FTY group but unchanged in the CsA group; 2) virus concentration was significantly higher in the CsA group but not in the FTY group; 3) expressions of IL-2, IL-12 and IFN-gamma in the heart were suppressed in both the FTY and CsA groups, though suppression was weaker in the FTY group; 4) TNF-alpha and NO were significantly increased in the CsA group but not in the FTY group.


CONCLUSIONS
FTY720 had a significant therapeutic effect in acute experimental myocarditis without inducing excessive virus replication. This report is the first to describe a beneficial effect by an immunosuppressive agent in the treatment of acute viral myocarditis.
Miyamoto
T
T
Department of Cardiovascular Medicine, Kyoto University, Japan.
Matsumori
A
A
Hwang
M W
MW
Nishio
R
R
Ito
H
H
Sasayama
S
S
D000208:Acute Disease; D000818:Animals; D018188:Cardiovirus Infections / Q000150:complications*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004686:Encephalomyocarditis virus; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000032:analysis; D018664:Interleukin-12 / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009205:Myocarditis / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000821:virology*; D009569:Nitric Oxide / Q000032:analysis; D016016:Proportional Hazards Models; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013110:Sphingosine / Q000031:analogs & derivatives; D016019:Survival Analysis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011409:Propylene Glycols; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine