T-cell co-stimulation by CD28-CD80/86 and its negative regulator CTLA-4 strongly influence accelerated atherosclerosis development
T-cell co-stimulation by CD28-CD80/86 and its negative regulator CTLA-4 strongly influence accelerated atherosclerosis development
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DOI：
10.1016/j.ijcard.2012.12.085
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发表时间：
2013-10-03
影响因子：
3.5
通讯作者：
Quax, P. H. A.
中科院分区：
文献类型：
--
作者：
Ewing, M. M.;Karper, J. C.;Quax, P. H. A.
目的：T 细胞是导致天然动脉粥样硬化的免疫反应的核心。本研究的目的是调查 T 细胞对干预后加速动脉粥样硬化发展的贡献，以及 CD28-CD80/86 共刺激和细胞毒性 T 淋巴细胞抗原 (CTLA)-4 共抑制途径在此过程中控制 T 细胞激活状态的作用。 方法和结果：T 细胞和 CD28-CD80/86 共刺激和在股动脉套囊小鼠模型中研究了 CTLA-4 共抑制途径，用于干预后重塑，血管内有显着的 CTLA-4+ T 细胞浸润。与正常 C57Bl/6J 对照相比，CD4(-/-) 和 CD80(-/-)CD86(-/-) 小鼠的内膜损伤减少。全身阿巴西普治疗是一种可溶性 CTLA-4Ig 融合蛋白，可防止 CD28-CD80/86 共刺激 T 细胞激活，可防止内膜增厚 58.5% (p=0.029)。接下来，高胆固醇血症 ApoE3*Leiden 小鼠接受阿巴西普治疗，可将加速的动脉粥样硬化发展减少 78.1% (p=0.040)，并预防CD4 T 细胞激活，表现为脾脏中激活的 KLRG1+、PD1+、CD69+ 和 CTLA-4+ T 细胞比例减少。这与血浆干扰素-γ 降低和白细胞介素 10 水平升高相关。使用 CTLA-4 阻断抗体证实了 CTLA-4 的作用，与同种型治疗的对照相比，该抗体使血管病变大小大幅增加 66.7% (p=0.008)。 结论：T 细胞 CD28-CD80/86 共刺激对于介入后加速动脉粥样硬化发展至关重要，并受 CTLA-4 共抑制的调节，表明在预防介入后动脉粥样硬化方面具有良好的临床潜力。通过阿巴西普进行重塑。 (C) 2013 Elsevier Ireland Ltd. 保留所有权利。
Objective: T-cells are central to the immune response responsible for native atherosclerosis. The objective of this study is to investigate T-cell contribution to post-interventional accelerated atherosclerosis development, as well as the role of the CD28-CD80/86 co-stimulatory and Cytotoxic T-Lymphocyte Antigen (CTLA)-4 co-inhibitory pathways controlling T-cell activation status in this process.Methods and results: The role of T-cells and the CD28-CD80/86 co-stimulatory and CTLA-4 co-inhibitory pathways were investigated in a femoral artery cuff mouse model for post-interventional remodeling, with notable intravascular CTLA-4+ T-cell infiltration. Reduced intimal lesions developed in CD4(-/-) and CD80(-/-)CD86(-/-) mice compared to normal C57Bl/6J controls. Systemic abatacept-treatment, a soluble CTLA-4Ig fusion protein that prevents CD28-CD80/86 co-stimulatory T-cell activation, prevented intimal thickening by 58.5% (p=0.029).Next, hypercholesterolemic ApoE3*Leiden mice received abatacept-treatment which reduced accelerated atherosclerosis development by 78.1% (p=0.040) and prevented CD4 T-cell activation, indicated by reduced splenic fractions of activated KLRG1+, PD1+, CD69+ and CTLA-4+ T-cells. This correlated with reduced plasma interferon-gamma and elevated interleukin-10 levels. The role of CTLA-4 was confirmed using CTLA-4 blocking antibodies, which strongly increased vascular lesion size by 66.7% (p=0.008), compared to isotype-treated controls.Conclusions: T-cell CD28-CD80/86 co-stimulation is vital for post-interventional accelerated atherosclerosis development and is regulated by CTLA-4 co-inhibition, indicating promising clinical potential for prevention of post-interventional remodeling by abatacept. (C) 2013 Elsevier Ireland Ltd. All rights reserved.