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EXPERIMENTAL STUDY

Nasal administration of cardiac myosin suppresses autoimmune myocarditis in mice

^a Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA, 21205
^b Department of Molecular Microbiology and Immunology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA, 21205

Manuscript received January 14, 2000; revised manuscript received May 18, 2000, accepted July 12, 2000.

Reprint requests and correspondence: Dr. Noel R. Rose, Department of Pathology, Ross 659, School of Medicine, Johns Hopkins University, 720 Rutland Avenue, Baltimore, Maryland 21205
nrrose{at}jhmi.edu

OBJECTIVES

This study was designed to examine whether myocarditis induced in a mouse model can be effectively suppressed by nasal administration of cardiac myosin (CM).

BACKGROUND

Myocarditis in humans often follows viral infection and is accompanied by evidence of an autoimmune response to CM. Treatment has been hampered by the fact that measures undertaken to reduce the autoimmune response often enhance the viral infection. Delivery of antigen via nasal route has been shown to induce antigen-specific tolerance and suppress certain autoimmune diseases in animal models.

METHODS

Myocarditis was induced in A/J mice by two subcutaneous injections of CM emulsified in complete Freund’s adjuvant. Nasal instillation of CM (200 µg/mouse) or vehicle buffer was carried out three days before the first subcutaneous injection (day –3). The effect of nasal instillation of CM on cardiac histopathology, cytokine production by splenocytes, and antibody response was examined three weeks after the first subcutaneous injection (day 21).

RESULTS

Nasal administration of CM effectively reduced the severity of myocarditis. Consistent with the histological findings, the levels of interleukin-2 (IL-2), tumor necrosis factor-, and IL-1ß produced by splenocytes in response to CM were significantly decreased. In addition, the serum levels of IgE and IgG1 anti-myosin antibodies were suppressed. However, the levels of transforming growth factor-ß (TGF-ß) and CM-specific IgA antibodies were not affected.

CONCLUSIONS

Taken together, our results do not support active suppression through upregulation of TGF-ß, IL-4, and IL-10 as a mechanism of tolerance, but favor anergy or deletion of both Th1 and Th2 autoreactive T cells.

Abbreviations and Acronyms   AChR = acetylcholine receptor   CM = cardiac myosin   CFA = complete Freund’s adjuvant   ConA = concanavalin A   EAE = experimental autoimmune encephalomyelitis   EAMG = experimental autoimmune myasthenia gravis   IFN- = interferon-   IL-1ß = interleukin-1ß   IL-2 = interleukin-2   IL-4 = interleukin-4   IL-10 = interleukin-10   MCM = murine cardiac myosin   PCM = porcine cardiac myosin   TGF-ß = transforming growth factor-ß   TNF- = tumor necrosis factor-

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