Immune responses to OxLDL and atherosclerosis

对 OxLDL 和动脉粥样硬化的免疫反应

• 批准号: 6577278
• 负责人: Joseph L. Witztum
• 金额: $ 29.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6577278
• 关键词: T cell receptor; antibody titering; apoptosis; atherosclerotic plaque; autoantibody; autoimmunity; cardiovascular disorder risk; clinical research; developmental immunology; genetically modified animals; human subject; humoral immunity; laboratory mouse; low density lipoprotein; low density lipoprotein receptor; macrophage; oxidative stress; oxidized lipid; passive immunization; scavenger receptor

DESCRIPTION (provided by the applicant): Oxidation of LDL renders it immunogenic and both humoral and cellular immune responses occur. Considerable evidence suggests that adaptive immune response to OxLDL are important: For example, OxLDL-specific T cells are present within lesions, and immunization of animal models with homologous OxLDL decreases the rate of progression of atherosclerosis. This Unit will test the following hypotheses: That certain adaptive immune response to epitopes of OxLDL can be beneficial; That there are human oxidation-specific autoantibodies that have similar properties to those cloned from apoE-deficient mice (i.e. the ability to affect macrophage uptake of OxLDL); That the presence of oxidized moieties on apoptotic cells render these cells immunogenic and proinflammatory; That the oxidation-specific antibodies can be used to detect rates of oxidation of LDL in vivo; and that various oxidation-specific markers in plasma are of clinical utility in identifying patients at increased risk for cardiovascular disease. We will test these hypotheses by determining the mechanisms by which immunization of hypercholesterolemic mice with MDA-LDL, as a model epitope of OxLDL, ameliorates atherosclerosis and specifically test the hypothesis that immunization causes a switch from a proatherogenic Th1 phenotype to an antiatherogenic Th2 phenotype. We will characterize T cell responses to the immunization with MDA-LDL and perform adoptive transfer experiments of T cell populations from immunized mice into naive mice and determine the effects on atherogenesis. We will also determine the components of MDA-LDL responsible for the protective effect. We will clone human oxidation- specific autoantibodies from an immunoglobulin phage display library and determine their biological properties. We will determine the epitopes on OxLDL and apoptotic cells recognized by antibodies that block uptake by macrophages, which in turn should bind to specific scavenger receptors. We will immunize mice with syngenic apoptotic cells and determine if they are immunogenic and if these cells induce monocyte binding to endothelial cells because of oxidized phospholipids on their surface. We will use immunological techniques to determine the in vivo rates of oxidation of LDL in vivo in animals and humans. Finally, we will examine general and high-risk populations to determine if various immunological markers of OxLDL are of clinical value in identifying individuals at increased risk for cardiovascular disease. In summary, these data should contribute to an improved understanding of the consequences of the immunogenicity of OxLDL.

描述(由申请人提供)： 氧化低密度脂蛋白使其具有免疫原性以及体液和细胞免疫功能 响应就会发生。大量证据表明，获得性免疫反应 对氧化低密度脂蛋白是重要的：例如，体内存在氧化低密度脂蛋白特异的T细胞 病变，用同源OxLDL免疫动物模型可降低 动脉粥样硬化的进展速度。本单元将测试以下内容 假设：对OxLDL表位的某些获得性免疫反应可能是 有益的；有人类氧化特异的自身抗体 与从apoE缺陷小鼠克隆的特性相似(即 影响巨噬细胞摄取氧化低密度脂蛋白)；氧化部分的存在 在凋亡细胞上使这些细胞具有免疫原性和促炎作用 氧化特异性抗体可用于检测细胞的氧化速率 体内的低密度脂蛋白；以及血浆中各种氧化特异性标志物 识别心血管疾病高危患者的临床实用价值 疾病。我们将通过确定这些假设的机制来检验这些假设 丙二醛-低密度脂蛋白作为模型表位免疫高胆固醇血症小鼠 氧化低密度脂蛋白，改善动脉粥样硬化，并专门测试假设 免疫可导致从致动脉粥样硬化的Th1表型转变为 抗动脉粥样硬化的Th2表型。我们将描述T细胞对 丙二醛-低密度脂蛋白免疫及T细胞过继转移实验 从免疫小鼠到幼鼠的种群并确定其对 动脉粥样硬化的形成。我们还将确定与丙二醛-低密度脂蛋白相关的成分 起到保护作用。我们将克隆人类氧化特异体 来自免疫球蛋白噬菌体展示文库的自身抗体 它们的生物学特性。我们将确定OxLDL和OXLDL的表位 被阻断巨噬细胞摄取的抗体识别的凋亡细胞， 它又应该与特定的清道夫受体结合。我们会给你接种 并确定它们是否具有免疫原性和 如果这些细胞诱导单核细胞与内皮细胞结合是因为 氧化的磷脂在其表面。我们将使用免疫学技术 测定动物体内低密度脂蛋白的体内氧化率 人类。最后，我们将检查普通人群和高危人群 确定氧化型低密度脂蛋白的各种免疫标志物是否具有临床价值 确定心血管疾病风险增加的个人。在……里面 总之，这些数据应该有助于更好地理解 氧化低密度脂蛋白免疫原性的后果。