Seko Y, Takahashi N, Oshima H, Shimozato O, Akiba H, Takeda K, Kobata T, Yagita H, Okumura K, Azuma M, Nagai R
Department of Cardiovascular Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
J Pathol. 2001 Dec;195(5):593-603. doi: 10.1002/path.986.
Antigen-specific T-cells infiltrate the heart and play an important role in the myocardial damage involved in acute myocarditis and dilated cardiomyopathy. 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 necrosis factor (TNF) receptor/ligand superfamily, in the development of acute viral 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 cultured 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. Thirdly, the effects of in vivo administration of anti-CD30L, anti-CD27L, anti-OX40L, 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-gamma in vitro. CD27L and OX40L were constitutively expressed on cardiac myocytes in vivo and in vitro. Anti-CD30L and anti-4-1BBL MAbs stimulated IL-6 production by cardiac myocytes in vitro. Furthermore, in vivo anti-4-1BBL MAb treatment significantly decreased the myocardial inflammation, whereas the other MAbs did not. These findings suggest that TNF ligand superfamily co-stimulatory molecules, especially 4-1BBL, play an important role in the development of acute viral myocarditis and raise the possibility that immunotherapy with anti-4-1BBL MAb may be of benefit in acute viral myocarditis.
抗原特异性T细胞浸润心脏，并在急性心肌炎和扩张型心肌病所涉及的心肌损伤中发挥重要作用。为了研究属于肿瘤坏死因子（TNF）受体/配体超家族的共刺激分子CD30/CD30L、CD27/CD27L、OX40/OX40L和4-1BB/4-1BBL在急性病毒性心肌炎发展过程中的作用，首先在体内对柯萨奇病毒B3（CVB3）诱导的急性心肌炎小鼠心脏中这些分子的表达进行了分析。其次，评估了用干扰素（IFN）-γ处理的培养心肌细胞上这些分子的诱导情况，并在体外通过用针对这些分子的单克隆抗体（MAb）刺激来分析培养心肌细胞产生白细胞介素（IL）-6的情况。第三，研究了体内给予抗CD30L、抗CD27L、抗OX40L或抗4-1BBL单克隆抗体对急性病毒性心肌炎发展的影响。CVB3诱导的心肌炎导致心肌细胞表面诱导表达CD30L和4-1BBL，体外经IFN-γ处理证实了这一点。CD27L和OX40L在体内和体外的心肌细胞上均组成性表达。抗CD30L和抗4-1BBL单克隆抗体在体外刺激心肌细胞产生IL-6。此外，体内抗4-1BBL单克隆抗体治疗显著减轻了心肌炎症，而其他单克隆抗体则没有。这些发现表明，TNF配体超家族共刺激分子，尤其是4-1BBL，在急性病毒性心肌炎的发展中起重要作用，并增加了用抗4-1BBL单克隆抗体进行免疫治疗可能对急性病毒性心肌炎有益的可能性。
