Expression of tumour necrosis factor (TNF) ligand superfamily co-stimulatory molecules CD30L, CD27L, OX40L, and 4-I BBL in murine hearts with acute myocarditis caused by Coxsackievirus B3

Antigen-specific T-cells infiltrate the heart and play an important role in the myocardial damage involved in acute myocarditis and dilated cardiomyop athy. To investigate the roles of the co-stimulatory molecules CD30/CD30L, CD27/CD27L, OX40/OX40L, and 4-1BB/4-1BBL, which belong to the tumor necrosi s factor (TNF) receptor/ligand superfamily, in the development of acute vir al myocarditis, the expression of these molecules was first analysed in the hearts of mice with acute myocarditis induced by Coxsackievirus B3 (CVB3) in vivo. Secondly, the induction of these molecules was evaluated on cultur ed cardiac myocytes treated with interferon (IFN)-gamma and the interleukin (IL)-6 production by cultured cardiac myocytes was analysed by stimulation with monoclonal antibodies (MAbs) against these molecules in vitro. Thirdl y, the effects of in vivo administration of anti-CD30L, anti-CD27L, anti-OX 40L, or anti-4-1BBL MAb on the development of acute viral myocarditis were examined. CVB3-induced myocarditis resulted in the induction of CD30L and 4 -1BBL on the surface of cardiac myocytes, confirmed by treatment with IFN-g amma in vitro. CD27L and OX40L were constitutively expressed on cardiac myo cytes in vivo and in vitro. Anti-CD30L and anti4-1BBL MAbs stimulated IL-6 production by cardiac myocytes in vitro. Furthermore, in vivo anti-4-1BBL M Ab treatment significantly decreased the myocardial inflammation, whereas t he other MAbs did not. These findings suggest that TNF ligand superfamily c o-stimulatory molecules, especially 4-1BBL, play an important role in the d evelopment of acute viral myocarditis and raise the possibility that immuno therapy with anti-4-1BBL MAb may be of benefit in acute viral myocarditis. Copyright (C) 2001 John Wiley & Sons, Ltd.