Expression of Costimulatory Molecule CD40 in Murine Heart With Acute Myocarditis and Reduction of Inflammation by Treatment With Anti-CD40L/B7-1 Monoclonal Antibodies

From the Third Department of Internal Medicine (Y.S., N.T., Y.Y.), Faculty of Medicine, University of Tokyo; the Department of Immunology (Y.S., H.Y., K.O.), School of Medicine, Juntendo University, Tokyo; the Institute for Adult Diseases (Y.S.), Asahi Life Foundation, Tokyo; and the Department of Immunology (M.A.), National Children's Medical Research Center, Tokyo, Japan.

Correspondence to Yoshinori Seko, MD, Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail sekoyosh-tky{at}umin.ac.jp

Abstract—Evidence has accumulated that antigen-specific T cells infiltrate the heart and play an important role in the pathogenesis of viral myocarditis. Costimulatory molecules such as B7s and CD40 expressed on antigen-presenting cells are known to play a critical role for antigen-specific T-cell activation to occur. To investigate the role for a costimulatory molecule, CD40, in the development of acute viral myocarditis, we first analyzed the expression of CD40 in the hearts of mice with acute viral myocarditis induced by Coxsackievirus B3. We also evaluated the induction of CD40 in cultured cardiac myocytes treated with interferon gamma in vitro. Second, we analyzed the cytokine production by cultured cardiac myocytes by stimulation with anti-CD40 monoclonal antibody (mAb) in vitro. Third, we examined the effects of in vivo administration of anti–CD40L/B7-1 mAbs on the development of acute viral myocarditis. We found that Coxsackievirus B3–induced murine acute myocarditis results in enhanced expression of CD40 on cardiac myocytes. The expression of CD40 on cardiac myocytes could be induced by interferon gamma in vitro. We also found that the production of interleukin-6 by cardiac myocytes was stimulated with anti-CD40 mAb and that in vivo anti–CD40L/B7-1 mAb treatment significantly decreased the myocardial inflammation. Our findings strongly suggest that CD40 plays an important role in the development of acute viral myocarditis and raise the possibility of immunotherapy with anti–CD40L/B7-1 mAbs to prevent T cell–mediated myocardial damage in viral myocarditis.

Key Words: myocarditis • cardiomyopathy • immunology • immunohistochemistry • polymerase chain reaction

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