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EXPERIMENTAL STUDY

Therapeutic effects of FTY720, a new immunosuppressive agent, in a murine model of acute viral myocarditis

^a Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan

Manuscript received October 10, 2000; revised manuscript received January 12, 2001, accepted January 29, 2001.

Reprint requests and correspondence: Dr. Akira Matsumori, Department of Cardiovascular Medicine, Kyoto University, 54 Kawaracho Shogoin, Sakyo-ku, Kyoto 606-8397, Japan
amat{at}kuhp.kyoto-u.ac.jp

OBJECTIVES

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.

Abbreviations and Acronyms   CsA = cyclosporine A   EMCV = encephalomyocarditis virus   FTY = FTY720   IFN = interferon   iNOS = inducible NO synthase   NO = nitric oxide   TNF = tumor necrosis factor

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