CELL MEDIATED IMMUNE MECHANISM IN ATHEROGENESIS

描述（由申请人提供）： 动脉粥样硬化病变是慢性炎症的部位， 有充分的证据表明，先天性和适应性免疫反应驱动了这一点。 炎症过程。活化的分泌干扰素-γ的Thl淋巴细胞是 早期和持续居民的动脉粥样硬化，但几个重要的 关于他们存在的问题没有得到解决。指导性假设 这些研究是Th 1细胞被选择性地募集到动脉粥样硬化中， 它们被抗原和共刺激分子特异性激活， Thl细胞促进巨噬细胞-泡沫细胞的活化，并且作为活化的结果，Thl细胞促进巨噬细胞-泡沫细胞的活化。 动脉病变的炎症病理学。该项目将侧重于 T淋巴细胞募集、活化和效应功能的机制 动脉粥样硬化病变的部位，根据三个具体目标。第一 Specific Aim将阐述T细胞募集至动脉粥样硬化的机制。 活体显微镜技术和TCR转基因T细胞群将 用于定义调节T细胞亚群特异性的分子相互作用 在离体灌流的小鼠颈动脉中与动脉粥样硬化病变的相互作用 动脉采用新开发的共培养物的补充实验 系统将定义T细胞-内皮相互作用如何受到 解剖学上并列的巨噬泡沫细胞。第二个具体目标将 检查T细胞的激活，重点是免疫功能的 巨噬细胞源性泡沫细胞。研究将检查脂质摄取的方式 和积累影响巨噬细胞抗原的加工和呈递 途径，巨噬细胞共刺激T细胞，和分泌细胞因子， 影响T细胞。在第三个具体目标中，T细胞的作用 将讨论动脉粥样硬化的激活。共刺激的作用 在T细胞对噬斑抗原的应答中， 在复合突变小鼠品系中进行研究。此外，鼠标线 将开发在内皮细胞上表达模型抗原，并用于 定义对该抗原特异性的效应和调节T细胞如何影响 动脉粥样硬化的发展。这些研究的结果应该 增强我们对动脉粥样硬化炎症性质的理解， 提出了治疗这种疾病免疫调节的策略。

DESCRIPTION (provided by applicant): The atherosclerotic lesion is a site of chronic inflammation, and there is ample evidence that the innate and adaptive immune responses drive this inflammatory process. Activated interferon-gamma secreting Thl lymphocytes are early and persistent residents of the atheroma, but several important questions about their presence are not resolved. The guiding hypotheses for these studies are that Thl cells are selectively recruited into atheromata, they are specifically activated by antigen and costimulators presented by the macrophage-foam cell, and as a result of activation, the Thl cells promote the inflammatory pathology of arterial lesions. This project will focus on the mechanisms of T lymphocytes recruitment, activation, and effector functions at the site of atherosclerotic lesions, under three Specific Aims. The First Specific Aim will address mechanisms of T cell recruitment to atheromata. Intravital microscopic techniques, and TCR transgenic T cell populations will be used to define the molecular interactions regulating T cell subset specific interactions with atherosclerotic lesions in isolated perfused mouse carotid arteries. Complementary experiments employing a newly developed coculture system will define how T cell-endothelial interactions are influenced by anatomically juxtaposed macrophage foam cells. The Second Specific Aim will examine activation of T cells, with a focus on the immune functions of the macrophage-derived foam cell. Studies will examine ways in which lipid-uptake and accumulation influences macrophage antigen processing and presentation pathways, macrophage costimulation of T cells, and secretion of cytokines that influence T cells. In the Third Specific Aim, the effects of T cell activation on atherosclerosis will be addressed. The role of costimulatory pathways and IFNgamma production in T cell responses to plaque antigens will be studied in compound mutant mouse lines. In addition, a mouse line expressing a model antigen on endothelial cells will be developed and used to define how effector and regulatory T cells specific for that antigen influence the development of atherosclerosis. The results of these studies should enhance our understanding of the inflammatory nature of atherosclerosis, and suggest strategies for therapeutic immumodulation of this disease.