Immune Mechanisms in Atherosclerosis

动脉粥样硬化中的MMUNE机制 项目负责人：Cornelia Weyand医学博士 联合调查者：Jorg J.Goronzy，医学博士 摘要 树突状细胞(DC)是捕捉和处理抗原以启动T细胞的哨兵。当定位在 慢性炎性组织损害，DC作为环境线索的传感器，并分化为 引导T淋巴细胞和单核细胞发育成熟为不同类型的免疫指导者 效应器类。两种不同的DC亚型，髓系DC和浆细胞样DC，填充在炎症中 与肩部T细胞相互作用的动脉粥样硬化斑块。每种DC类型都配备了 通过一组独特的模式识别受体，Toll样受体(TLR)，它们通过这些受体检查 危险信号的微环境，如病原体衍生的模体、细胞碎片和修饰 代谢物(如oxLDL)。最终，原始DC触发器和DC类型将决定强度， 持续时间，以及由此产生的免疫反应的特征。此应用程序旨在理解 选择性TLR触发对斑块包埋DC及其功能的影响 对T细胞和巨噬细胞分化、血管平滑肌细胞(VSMC)命运的影响 动脉硬化斑块的稳定性。鉴于DC在炎症级联中的顶端位置，以及 耐受树突状细胞下调免疫应答的潜力，我们将探索分子机制 斑块内的DC可通过其抑制斑块炎症，重新稳定病变。通过使用完整的 人颈动脉粥样硬化和SCID嵌合体植入人类动脉粥样硬化，我们将在特定的 目的1选择性DC激活如何对斑块浸润性T细胞的效应功能给予不同的指导 细胞和巨噬细胞。具体来说，我们将研究TLR介导的DC触发对T细胞的影响 招募和存活，对Th1和Th17效应者类别的承诺，T细胞细胞毒的诱导和 组织损伤巨噬细胞功能的协调。《特定目标2》旨在研究这一假说。 DC刺激最终决定斑块VSMC的命运。我们将重点介绍如何引导 促炎症细胞因子、金属蛋白酶、NADPH氧化酶和死亡受体DR5的表达 作为细胞凋亡敏感性的决定因素。特指目标3致力于开发新型免疫调节剂 以抑制斑块炎症和不稳定为目标的治疗。以初步数据为基础 CD80/CD86与可溶性诱骗受体CTL_A4-LG结合可诱导细胞色氨酸耗竭 斑块组织和抑制细胞损伤，我们将针对斑块驻留的DC将它们转化为色氨酸 分解代谢和免疫抑制细胞。我们将探索CTLA4-LG介导的组织保护 直接抑制组织破坏性效应细胞的结果，或者它是否涉及生成和扩增 抗炎的CD25h‘9hFoxp3T调节(Treg)细胞。机械实验，利用 在人类动脉粥样硬化-SCID嵌合体中的过继转移，将解决应激激酶GCN2作为一种 Treg诱导的分子介体。

MMUNE MECHANISMS IN ATHEROSCLEROSIS PROJECT LEADER: Cornelia Weyand, M.D. CO-INVESTIGATOR: Jorg J. Goronzy, M.D. ABSTRACT Dendritic cells (DC) are sentinels that capture and process antigens to prime T cells. When positioned in chronic inflammatory tissue lesions, DC function as sensors of environmental cues and differentiate into "immune instructors" that guide the development and maturation of T lymphocytes and monocytes into distinct effector classes. Two different DC subtypes, myeloid DC and plasmacytoid DC, populate the inflamed atherosclerotic plaque where they interact with T cells in the shoulder region. Each of the DC types is equipped with a distinct set of pattern recognition receptors, Toll-like receptors (TLR), through which they inspect the microenvironment for danger signals, such as pathogen-derived motifs, cellular debris, and modified metabolites (e.g. oxLDL). Ultimately, the original DC trigger and the DC type will determine the intensity, duration, and character of resulting immune responses. This application is designed to understand mechanistically the impact of selective TLR triggering on plaque-embedded DC and the functional consequences for T cell and macrophage differentiation, vascular smooth muscle cell (VSMC) fate, and stability of the atherosclerotic plaque. Given the position of DC at the top of the inflammatory cascade and the potential of tolerogenic DC to downregulate immune responses, we will explore molecular mechanisms through which plaque-residing DC can dampen plaque inflammation and restabilize the lesion. By using intact human carotid atheroma and SCID chimeras implanted with human atheroma, we will investigate in Specific Aim 1 how selective DC activation confers differential instruction of effector functions in plaque-infiltrating T cells and macrophages. Specifically, we will study the consequences of TLR-mediated DC triggering on T-cell recruitment and survival, commitment to the Th1 vs. Th17 effector class, induction of T-cell cytotoxicity and orchestration of tissue-injurious macrophage functions. Specific Aim 2 is designed to investigate the hypothesis that DC stimulation ultimately regulates the fate of plaque VSMC. We will focus on induction of proinflammatory cytokines, metalloproteinases, NADPH oxidases, and expression of the death receptor DR5 as determinants of apoptosis sensitivity. Specific Aim 3 is devoted to developing novel immunomodulatory therapies with the goal of suppressing plaque inflammation and instability. Building on preliminary data showing that ligation of CD80/CD86 with the soluble decoy receptor CTl_A4-lg induces tryptophan depletion in plaque tissue and suppresses cellular injury, we will target plaque-residing DC to turn them into tryptophan catabolizing and immunosuppressive cells. We will explore whether CTLA4-lg-mediated tissue protection results from direct inhibition of tissue-damaging effector cells or whether it involves generation and expansion of anti-inflammatory CD4+CD25h'9hFoxp3+ T regulatory (Treg) cells. Mechanistic experiments, making use of adoptive transfers in human atheroma-SCID chimeras, will address the role of the stress kinase GCN2 as a molecular mediator of Treg induction.