动脉粥样硬化疾病在瑞典和中国均是健康护理的重大负担。这个合作研究联合瑞士和中国的研究者，加强在动脉粥样硬化中炎症和血栓形成相互作用的机制探讨。这次合作促使我们探讨血小板调节的 CD4+ T 细胞在人和小鼠及体内外的应答。本课题提高我们对血栓形成和炎症相互作用的理解，为动脉粥样硬化中血小板调节炎症反应的过程提供了新的视野。我们的工作或许能找出血小板调节炎症过程中的潜在干预靶点，为更好的治疗动脉血栓性疾病提供更有价值的信息。. 这次研究合作使所有参与研究者的研究优势互补,创建了一次良好的瑞典和中国研究人员的协同合作。双方的合作会带来附加价值并提高研究质量和生产效率。另外，本项目加强并扩展了卡罗林斯卡医学院和山东大学的研究和研究教育合作并为中瑞两国在科学和医疗保健合作的快速发展做出积极贡献。

Atherosclerosis is a chronic disease of arterial vessel wall. Atherogenesis often starts in adolescent, and slowly develops into clinically manifest cardiovascular diseases, including ischemic heart disease, stroke, peripheral intermittent claudication. Atherosclerotic cardiovascular diseases are the number one morbidity and mortality cause not only in Western countries but also in China, for which changes of lifestyle and environmental factors are known to have a major impact on the increase of atherosclerotic cardiovascular diseases. There is a recent report (IJC Heart & Vasculature 2015;6:25) showing that there were 230 million Chinese, approximately 15% of the total population, suffering from cardiovascular diseases, and that cardiovascular diseases accountedfor 41% cause of mortality in 2011. The figures represent a dramatic epidemiological change of atherosclerotic diseases in China, which are closely linked to the significant changes in lifestyle (e.g., sedentary lifestyle), Westernized/high-fat diet, and environment (air and water pollution) coming alone with last three-decade’s economic boom. Obviously, atherosclerotic cardiovascular diseases are chronic diseases that cast major burdens for the healthcare and social welfare systems in Sweden and China and in the world. Therefore, it is an urgent task for our societies to improve our current anti-atherosclerotic disease treatments and to develop new drugs and novel therapies against atherosclerotic diseases.. Platelet activation and thrombosis play important roles throughout all development stages of atherosclerosis. Hence, antiplatelet treatment has long been recognized as a corner stone of the management of atherosclerotic diseases, typically for acute coronary syndromes. Current antiplatelet drugs target platelet activation per se, representing by the COX-inhibitor aspirin and the ADP receptor antagonist clopidogrel or ticagrelor. These antiplatelet drugs provide approximately 30-40% protection for the secondaryprevention of acute coronary syndrome patients. However, therapies of these antiplatelet drugs have reached the limit of their therapeutic window, due to bleeding risks. On the other hand, the protection by these antiplatelet drugs for the primary prophylactics of ischemic heart disease does not outweigh their bleeding risks. Thus, there is a clear need for an optimized treatment for atherosclerotic cardiovascular diseases.. Atherosclerosis development involves multiple mechanisms, including inflammation, thrombosis, and disorders of lipid metabolism. To improve the management of the chronic disease, there are ongoingfierce research campaigns against atherosclerosis. For example, research on atherosclerosis-targeted vaccination for the primary prophylactics of atherosclerotic diseases is being carried out by some of the Swedish researchersin the present team of Sino-Swedish collaborative research. There are also active research and therapeutic developmentsin antiplatelet drugs with no bleeding risks. On the other hand, atherosclerosis is not only an inflammatory disease but also a thrombotic disease. Inflammatory and thrombotic mechanisms, as well as their cross-talk are closely involved in atherogenesis. Therefore, better understanding of thrombosis-inflammation cross-talk may identify intervention sites of the cross-talk, i.e., plateletregulated CD4+ T effector cell responses in the present collaborative research, for novel anti-atherosclerotic therapeutic developments. The new platelet-regulated CD4+ T effector cell response targeted therapy will bring about good additive or even synergistic effects on classical antiplatelet therapies with COX or/and ADP P2Y12 receptor inhibitors. The dual therapy targeting platelet activation per se and platelete-regulated inflammatory mechanisms may thus significant improve the primary and secondary prevention of atherosclerotic diseases. Therefore, the present Sino-Swedish collabor.

1. 探讨在动脉粥样硬化形成过程中血小板调节的炎症机制，找出干预动脉粥样硬化疾病中血小板调节的炎症的潜在干预靶点，寻找新的治疗策略。 2. 合作项目的具体目研究目标与内容： 目标一：血小板调节的不同效应细胞激活不同的CD4+T细胞亚群。 目标二：体内血小板调节性CD4+ T 细胞的激活与分化。 目标三：血小板来源的TGFβ对CD4+ T 细胞功能的影响在体内以及动脉粥样硬化中的重要性。3.我们已完成的工作显示血小板根据不同的动力学调节CD4+ T 细胞应答，对Th1 和 Th17应答细胞呈现双向调节作用，对Treg细胞应答呈现持续增强的作用11。我们的研究主要的目的是为了探讨血小板如何对不同的CD4+ T 亚群发挥不同的调节作用，也就是分离出每个CD4+ T 的亚群。因此，我们将用MACS阴性分选技术分离出CCR7+CD45RA+，CCR7+CD45RA-和CCR7-CD45RA- CD4+ T细胞亚群.这三种细胞在存在或缺失自体血小板的情况下用CD3/CD28细胞刺激。. CD4+ T效应器，Treg表型和他们产生的相应的细胞因子将被检测长达2周，以便研究血小板调节的CD4+ T亚群应答的不同性。而且，血小板的调节呈现双向的作用，例如对T效应器应答发挥短暂的增强后抑制的作用11。我们假设不同血小板来源的调节者解释不同阶段的T效应细胞应答。因为血小板释放T效应细胞的激动剂（像RANTES 和 PAF）和抑制剂(TGFβ 和 PF4) 4，所以我们假设RANTES 和 PAF负责血小板调节的T效应细胞应答的第一/增强阶段，而 TGFβ 和 PF4负责其第二/抑制阶段。这个假设将被分离出的Th1和Th17细胞用血小板或其调节因子相对应的中和抗体或受体激动剂来刺激给予验证。找出其中的调节因子后，下一步探讨血小板来源的调节因子是如何影响T应答细胞细胞间信号机制的，包括NF-B动员和转录因子激活 (Th1:T-bet 和Th17:RORt)等。4. 合作项目已取得的重要成果： 卡罗林斯卡已经有的博士研究生来山东大学心血管功能与重构研究教育部与卫生部重点实验室开展半年的研究工作，双方已在相关专业期刊发表学术论文2篇。