Attenuation of experimental autoimmune myocarditis by blocking activated T cells through inducible costimulatory molecule pathway
Attenuation of experimental autoimmune myocarditis by blocking activated T cells through inducible costimulatory molecule pathway
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DOI：
10.1016/s0008-6363(03)00334-1
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发表时间：
2003-07-01
影响因子：
10.8
通讯作者：
Uede, T
中科院分区：
文献类型：
--
作者：
Futamatsua, H;Suzuki, J;Uede, T
目的：诱导共刺激因子（ICOS）是CD28家族的成员。虽然炎症是心肌炎的基本病理特征。ICOS在心肌炎中的作用尚不清楚。方法与结果：采用纯化猪心肌球蛋白免疫Lewis大鼠，建立实验性自身免疫性心肌炎（EAM）模型。流式细胞术检测心肌浸润细胞中ICOS的表达。静脉注射抗icos抗体或icos免疫球蛋白（ICOSIg）。分别于第14天和第21天处死大鼠，研究ICOS/ICOS-配体（ICOSL）通路阻断在抗原启动期（0-14天）和免疫应答期（14-21天）的影响。测定心脏重量与体重比，并进行组织学检查和超声心动图检查，以评估疾病的严重程度。分析心肌细胞因子的表达及T细胞对心肌肌球蛋白的增殖。流式细胞术显示浸润细胞以cd4阳性细胞居多。国际安全和发展理事会表示。在免疫应答阶段阻断ICOS/ICOSL通路可减弱EAM的发展。然而。在体外实验中，通过ICOS阻断T细胞活化可抑制inf - γ、IL-4、IL-6、IL-10、il -1 β和tnf - α等细胞因子的表达，抑制T细胞增殖。结论：在免疫应答阶段通过ICOS阻断T细胞活化可调节EAM的发展，因此ICOS可能是治疗心肌炎的有效靶点。(C) 2003年欧洲心脏病学会。Elsevier Science B.V.版权所有。
Objective: Inducible costimulator (ICOS) is a member of the CD28 family. Although inflammation is an essential pathological feature of myocarditis. the role of ICOS in myocarditis remains unclear. Methods and Results: Lewis rats were immunized on day 0 with purified porcine cardiac myosin to establish experimental autoimmune myocarditis (EAM). Flow cytometry was used to examine expression of ICOS on myocardial infiltrating cells. Anti-ICOS antibody or ICOS-immunoglobulin (ICOSIg) was administered intravenously. and rats were killed on day 14 or 21 to study effects of ICOS/ICOS-ligand (ICOSL) pathway blockade during the antigen priming phase (days 0-14) or immune response phase (days 14-21), respectively. The heart weight to body weight ratio was determined, and histological examination and echocardiogram were performed to evaluate the severity of the disease. Cytokine expression in the heart and T cell proliferation against cardiac myosin were analyzed. Flow cytometry revealed that the majority of infiltrating cells, especially CD4-positive cells. expressed ICOS. Blockade of the ICOS/ICOSL pathway during the immune response phase attenuated EAM development. However. blockade of the ICOS/ICOSL pathway during the antigen priming phase did not attenuate and exacerbate EAM, Blockade of T cell activation through ICOS Suppressed expression of cytokines including INF-gamma, IL-4, IL-6, IL-10, IL-1beta, and TNF-alpha and inhibited T cell proliferation in vitro. Conclusions: Blockade of T cell activation through ICOS during the immune response phase regulates development of EAM and therefore, ICOS may be an effective target for treating myocarditis. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.