Immune Mechanisms in Atherosclerosis

动脉粥样硬化的免疫机制

• 批准号: 8337807
• 负责人: Cornelia M. Weyand
• 金额: $ 27.84万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8337807
• 关键词: Address; Adoptive Transfer; Angiotensin II; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Biology; Blood Vessels; Blood flow; CD80 gene; CTLA4 gene; Cardiovascular Diseases; Carotid Artery Ulcerating Plaque; Cell physiology; Cells; Cessation of life; Chimera organism; Chronic; Cues; Data; Dendritic Cells; Dendritic cell activation; Development; Effector Cell; Environment; Generations; Goals; Human; Immune; Immune response; Immune system; Immunosuppressive Agents; Implant; Infection; Inflammation; Inflammatory; Instruction; Interphase; Lesion; Ligation; Mediating; Mediator of activation protein; Metalloproteases; Molecular; Myelogenous; Myocardial Infarction; NADPH Oxidase; Oxidative Stress; Oxidative Stress Pathway; Patients; Pattern recognition receptor; Phosphotransferases; Positioning Attribute; Regulatory T-Lymphocyte; Research Personnel; Resource Sharing; Role; Rupture; Sentinel; Shoulder; Signal Transduction; Smooth Muscle Myocytes; Stress; Stroke; T-Lymphocyte; TNFRSF10B gene; Tissues; Toll-like receptors; Tryptophan; Wound Healing; acute coronary syndrome; antigen processing; cell injury; cell type; cytokine; cytotoxicity; design; instructor; macrophage; monocyte; novel; novel therapeutic intervention; oxidant stress; pathogen; receptor; research study; sensor; success

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.

树突状细胞（DC）是捕获抗原并将其加工成初始T细胞的哨兵。当定位于