CD4+ T CELLS PROMOTE EARLY ATHEROSCLEROSIS

描述(摘自研究人员摘要)：临床动脉粥样硬化 涉及慢性低度炎症，牵涉到免疫介质在 心血管疾病(CVD)。T淋巴细胞约占20% 动脉粥样硬化纤维帽中的细胞，以及尽管有争议的小鼠 T细胞缺陷导致的主动脉病变比免疫活性小 动物。细胞因子是多种营养因子，可影响许多不同类型的 细胞，并具有各种生物效应。T细胞可按以下分类： 它们产生的细胞因子的类型。Th1细胞产生干扰素、IL-2和肿瘤坏死因子，而Th2细胞 细胞产生IL-4、IL-6和IL-10。许多因素影响Th细胞偏置和 确定主导亚型反应。这些因素包括：细胞因子环境 在Th0细胞激活过程中，抗原提呈细胞的类型，其主要 组织相容性复合体(MHC)II类抗原单倍型，表达 辅助分子如B7-1/B7-2、T细胞的浓度和类型 表位，以及其他调控细胞的存在，如天然的 表达T细胞受体的杀伤细胞和T淋巴细胞。在许多 疾病、易感性或抗性对应于其中一种的显性 Th1或Th2细胞应答。申请者假设在小鼠体内 动脉粥样硬化，偏向Th1细胞导致易感性，而偏向Th2细胞 偏见会增加抵抗力。PI将通过调制Th来确认这一假设 使用三种不同的方法偏向Th1或Th2表型。 特异性靶点1通过外源性给药调节免疫偏离 IL-12(Th1诱导)或IL-4(Th2诱导)细胞因子或使用细胞因子 基因敲除老鼠。特定目标2将使用辐射嵌合小鼠在 转IA和IEⅡ类MHC分子的C57BL/6菌株。MHC类 II IA分子与Th1偏向和动脉粥样硬化相关 易感性，而IE分子与Th2偏向和心血管疾病有关 抵抗。特异靶3将研究CD4+T细胞在 并评估这些细胞是否促进Th1细胞优势。

DESCRIPTION (Adapted from Investigator's Abstract): Clinical atherosclerosis involves chronic low-grade inflammation, implicating immune mediators in cardiovascular disease (CVD). T lymphocytes comprise approximately 20 percent of the cells in the atheroma fibrous cap, and, although controversial, mice deficient in T cells develop smaller aortic lesions than immunocompetent animals. Cytokines are pleiotrophic factors that affect many different types of cells and have various biological effects. T cells can be categorized by the types of cytokines they produce. Th1 cells make IFN, IL-2 and TNF, whereas Th2 cells make IL-4, IL-6, and IL-10. Many factors influence Th cell bias and determine dominant subtype response. These include: the cytokine environment during Th0 cell activation, the type of antigen-presenting cell, its major histocompatibility complex (MHC) class II antigen haplotype, expression of accessory molecules such as B7-1/B7-2, the concentration and type of T cell epitope, and the presence of additional regulatory cells, such as natural killer cells and T lymphocytes expressing the T cell receptor. In many diseases, susceptibility or resistance corresponds to the dominance of either Th1 or Th2 cell responses. The applicant hypothesizes that in murine atherosclerosis, a Th1 cell bias confers susceptibility, whereas, a Th2 cell bias promotes resistance. The PI will confirm this hypothesis by modulating Th bias towards either the Th1 or Th2 phenotype using three distinct methods. Specific Aim 1 will modulate immune deviation by exogenous administration of IL-12 (Th1-inducing) or IL-4 (Th2-inducing) cytokines or by using cytokine knockout mice. Specific Aim 2 will use irradiation chimeric mice made between C57BL/6 strains transgenic for IA and IE class II MHC molecules. The MHC class II IA molecule is associated with a Th1 bias and atherosclerosis susceptibility, whereas, the IE molecule is associated with Th2 bias and CVD resistance. Specific Aim 3 will investigate the role of CD4+ T cells in atherogenesis and evaluate whether these cells promote Th1 cell dominance.