Vascular Biology and Atherosclerosis Laboratory, BakerIDI Heart and Diabetes Institute, Melbourne, Australia.
Circulation. 2012 Sep 4;126(10):1256-66. doi: 10.1161/CIRCULATIONAHA.112.099044. Epub 2012 Jul 31.
CD4+CD25+Foxp3+ regulatory T cells (Tregs) attenuate atherosclerosis, but their therapeutic application by adoptive transfer is limited by the need for their expansion in vitro and limited purity. Recently, an interleukin (IL)-2/anti-IL-2 neutralizing monoclonal antibody (IL-2/anti-IL-2 mAb) complex has been shown to expand these Tregs. We examined the capacity of a modified IL-2/anti-IL-2 mAb treatment to expand Tregs and inhibit both the progression and development of developed atherosclerosis.
Six-week old apolipoprotein E-deficient mice fed a high-fat diet for 8 weeks were administered IL-2/anti-IL-2 mAb commencing 2 weeks after starting the diet. Tregs in the spleen, lymph node, and liver were selectively expanded without affecting CD4+, CD8+, or natural killer cells. Tregs were increased in lesions and lesion size reduced. CD4+ T-cells, macrophages, mature dendritic cells, proliferating cell nuclear antigen+ cells, and monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 were reduced. In anti-CD3-stimulated splenocytes, proliferation and secretion of Th1, Th2, and Th17 (IL-17) cytokines and IL-1β were reduced. To determine whether treatment attenuated progression of developed atherosclerosis, 6-week-old apolipoprotein E-deficient mice were fed a high-fat diet for 6 weeks, followed by IL-2/anti-IL-2 mAb treatment for 6 weeks while continuing the high-fat diet. Treatment also increased Tregs without affecting CD4+, CD8+, or natural killer cells, suppressed inflammation, and greatly attenuated progression of atherosclerosis.
IL-2/anti-IL-2 mAb treatment in vivo attenuates atherosclerosis via selective Tregs expansion. The findings suggest that cytokine-based IL-2/anti-IL-2 mAb complex therapy could represent an attractive approach for treating atherosclerosis, because it markedly attenuates progression as well as development, by modulating its immunoinflammatory component.
CD4+CD25+Foxp3+调节性 T 细胞（Tregs）可减轻动脉粥样硬化，但由于需要在体外扩增以及纯度有限，其过继转移的治疗应用受到限制。最近，一种白细胞介素（IL）-2/抗 IL-2 单克隆抗体（IL-2/抗 IL-2 mAb）复合物已被证明可扩增这些 Tregs。我们研究了改良的 IL-2/抗 IL-2 mAb 治疗方法扩增 Tregs 的能力，并抑制已发展的动脉粥样硬化的进展和发展。
6 周龄载脂蛋白 E 缺陷小鼠高脂饮食喂养 8 周，饮食开始后 2 周开始给予 IL-2/抗 IL-2 mAb。脾、淋巴结和肝脏中的 Tregs 选择性扩增，而不影响 CD4+、CD8+或自然杀伤细胞。病变中 Tregs 增加，病变缩小。CD4+T 细胞、巨噬细胞、成熟树突状细胞、增殖细胞核抗原+细胞、单核细胞趋化蛋白-1 和血管细胞黏附分子-1 减少。在抗 CD3 刺激的脾细胞中，Th1、Th2 和 Th17（IL-17）细胞因子和 IL-1β的增殖和分泌减少。为了确定治疗是否减轻已发展的动脉粥样硬化的进展，6 周龄载脂蛋白 E 缺陷小鼠高脂饮食喂养 6 周，然后继续高脂饮食，同时给予 IL-2/抗 IL-2 mAb 治疗 6 周。治疗还增加了 Tregs，而不影响 CD4+、CD8+或自然杀伤细胞，抑制炎症，并大大减轻动脉粥样硬化的进展。
体内 IL-2/抗 IL-2 mAb 治疗通过选择性 Tregs 扩增减轻动脉粥样硬化。这些发现表明，基于细胞因子的 IL-2/抗 IL-2 mAb 复合物治疗可能是治疗动脉粥样硬化的一种有吸引力的方法，因为它通过调节其免疫炎症成分，显著减轻进展和发展。
