Immune Mechanisms in Atherosclerosis

动脉粥样硬化的记忆机制 项目负责人：科尔内利亚Weyand，医学博士 共同研究员：Jorg J. Goronzy，医学博士 摘要 树突状细胞（DC）是捕获和加工抗原以引发T细胞的哨兵。当被定位在 慢性炎性组织病变，DC作为环境线索的传感器起作用，并分化为 “免疫指导者”引导T淋巴细胞和单核细胞发育和成熟为不同的免疫细胞。 效应器类。两种不同的DC亚型，髓样DC和浆细胞样DC，分布在发炎的 动脉粥样硬化斑块，在那里他们与T细胞在肩部地区。每种DC类型都配备了 与一组独特的模式识别受体，Toll样受体（TLR），通过它，他们检查 危险信号的微环境，如病原体衍生的基序，细胞碎片和修饰的 代谢物（如oxLDL）。最终，原始DC触发器和DC类型将决定强度， 持续时间和所产生的免疫应答的特征。此应用程序旨在了解 在机制上，选择性TLR触发对斑块嵌入的DC的影响和功能性TLR触发对斑块嵌入的DC的影响。 T细胞和巨噬细胞分化的后果，血管平滑肌细胞（VSMC）的命运， 稳定动脉粥样硬化斑块。鉴于DC在炎症级联反应的顶部的位置， 潜在的致耐受性DC下调免疫反应，我们将探讨分子机制 通过该途径，斑块驻留的DC可以抑制斑块炎症并重新稳定病变。通过使用完整的 人颈动脉粥样硬化和植入人粥样硬化的SCID嵌合体，我们将在特定的 目的1选择性DC激活如何在斑块浸润性T细胞中赋予效应子功能的差异指示， 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。 募集和存活，对Th 1与Th 17效应物类别的承诺，T细胞细胞毒性的诱导， 组织损伤性巨噬细胞功能的协调。具体目标2旨在研究假设 DC刺激最终调节斑块VSMC的命运。我们将重点介绍 促炎细胞因子、金属蛋白酶、NADPH氧化酶和死亡受体DR 5的表达 作为细胞凋亡敏感性的决定因素。Specific Aim 3致力于开发新型免疫调节剂 目的是抑制斑块炎症和不稳定性。根据初步数据 显示了CD 80/CD 86与可溶性诱饵受体CT1_A4-Ig的连接诱导色氨酸耗竭， 斑块组织和抑制细胞损伤，我们将靶向斑块驻留DC，将其转化为色氨酸 分解代谢和免疫抑制细胞。我们将探讨CTLA 4-Ig介导的组织保护作用是否 是否直接抑制组织损伤效应细胞或是否涉及产生和扩增 抗炎性CD 4 + CD 25 h-9 hFoxp 3 + T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GCN 2作为一种免疫调节剂的作用。 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.