The role of T cell response to antigenic ApoB-100 peptides in vaccination strategies against atherosclerosis

动脉粥样硬化是血管壁的慢性炎症性疾病。其临床并发症，如冠心病、心肌梗死和中风是全球死亡的主要原因。尽管在表征潜在的炎症机制方面取得了相当大的进展，例如免疫细胞浸润的准确描述，但还没有抗炎策略可以转化为临床可用的治疗。从免疫学的角度来看，炎症反应代表了动脉粥样硬化斑块中许多细胞和分子相互作用的终点。大量证据表明，T细胞在炎症反应的启动中识别特异性抗原。有人提出，低密度脂蛋白（LDL）和它们的主要蛋白质组分，如载脂蛋白（Apo）B-100，代表这样的自身抗原。根据动脉粥样硬化中自身免疫反应的概念，针对某些自身抗原的疫苗接种方法已在一些动物试点研究中得到验证，但细胞或分子特性、机制或后果均未阐明。特别是，一些有趣的问题还没有得到回答：是动脉粥样硬化免疫后修饰的脂质和抗原肽引起的保护性T细胞亚群的初级诱导或二级的保护性自身抗体对抗原肽的产生。此外，抗原特异性疗法在临床实践中还不可用。在宿主机构的最新创新，例如在小鼠中赋予动脉粥样硬化保护的小鼠ApoB-100的确切抗原序列的鉴定和检测单一抗原T细胞的新可能性，引起了申请人的工作计划。特别是，工作计划的目的是澄清是否与小鼠ApoB-100肽免疫调节细胞因子和CD 4 + T细胞分化成不同的TH效应谱系和描述免疫调节T辅助细胞效应功能在体外和体内。此外，致耐受性树突状细胞和调节性T细胞在动脉粥样硬化保护中的确切功能作用以及针对抗原肽的自身抗体的作用也将得到解决。几个基因敲除和转基因动物模型，过继转移实验和一种新的活细胞成像方法来检测抗原性T细胞离体和体内将被采用。所示的工作计划将为针对Apo B-100的疫苗接种的机制和后果提供新的功能性见解。所要求的工作计划是将疫苗接种战略转化为临床实践的最终目标所必需的。

Atherosclerosis is a chronic inflammatory disease of the vessel wall. Its clinical complications, such as coronary heart disease, myocardial infarction, and stroke represent the leading cause of mortality worldwide. Despite considerable progress in the characterization of underlying inflammatory mechanism, such as the exact description of immune cell infiltration, no anti-inflammatory strategy could be translated into a clinically available therapy yet. From an immunological view, the inflammatory response represents the endpoint of many cellular and molecular interactions in the atherosclerotic plaque. A solid body of evidence implicates specific antigen recognition by T cells in the initiation of the inflammatory response. It was proposed that low-density lipoproteins (LDL) and their main protein components, such as Apolipoprotein (Apo) B-100, represent such auto-antigens. In line with the concept of an autoimmune response in atherosclerosis, vaccination approaches against some auto-antigens have been validated in some animal pilot studies, but neither cellular or molecular properties, mechanisms or consequences were clarified. In particular, some intriguing questions have not been answered: Is atheroprotection after immunization with modified lipids and antigenic peptides caused by a primary induction of a protective T cell subset or secondary by generation of protective auto-antibodies against antigenic peptides. Also, an antigen-specific therapy is not yet available in clinical practice. Recent innovation at the host institution, such as the identification of the exact antigen sequences of mouse ApoB-100 that confer atheroprotection in mice and the novel possibility to detect single antigenic T cells gave rise to the applicants working plan. In particular, the working plan was designed to clarify whether immunization with mouse ApoB-100 peptides modulates cytokine and differentiation profiles of CD4+ T cells into distinct TH-effector lineages and to describe how immunization regulates T-helper cell effector function in vitro and in vivo. Moreover, the exact functional role of tolerogenic dendritic cells and T-regulatory cells in conferring atheroprotection and the role of auto-antibodies against antigenic peptides will be addressed. Several genetic knock-out and transgenic animal models, adoptive transfer experiments and a novel live cell imaging approach to detect antigenic T cells ex vivo and in vivo will be employed. The indicated working plan will provide novel functional insight into mechanisms and consequences of vaccination against Apo B-100. The requested working plan is required for the ultimate goal of translating vaccination strategies into clinical practice.