GUT-DERIVED IMMUNE EFFECTOR CELLS

肠道来源的免疫效应细胞

• 批准号: 7176934
• 负责人: JOHN R KLEIN
• 金额: $ 23.15万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-04-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7176934
• 关键词: Address; Apoptosis; Appearance; Autoimmunity; CD3 Antigens; CD8B1 gene; Cell Death; Cessation of life; Chronic; Development; Disease; Effector Cell; Evaluation; Event; Funding; Gene Proteins; Goals; Grant; Immune; Immune response; Immunity; Infection; Inflammation; Inflammatory; Inflammatory disease of the intestine; Interferon-alpha; Intervention Studies; Intestines; Laboratories; Link; Lymphocyte; Malignant Neoplasms; Maps; Modeling; Molecular; Mus; Nature; Numbers; Pathway interactions; Phase; Process; Property; Protein Array; Range; Recommendation; Research Personnel; Role; Series; Signal Transduction; Small Intestines; Staging; T-Lymphocyte; Testing; Therapeutic Intervention; Ursidae Family; base; chemokine; cytokine; design; in vivo; intestinal epithelium; intraepithelial; research study; response

This is a continuation of a project, for which the long-term goal is to define T cell effector mechanisms at the level of the small intestinal epithelium, by characterizing the stimulatory and costimulatory signals that drive intestinal intraepithelial lymphocytes (lELs) through activation. The central hypothesis for these studies is that small intestinal lELs are partially-activated T cells that can be rapidly driven to express additional effector activities through an ordered process of costimulatory activation, and that the nature and magnitude of the effector responses generated are the direct consequence of those activation signals. There are four integrated Specific Aims. Aim 1: To characterize the costimulatory effects of CD43 S7+ and S7- lELs with regard to apoptosis, death-proneness, and activation-induced cell death; to define the role of CD43 on IEL proliferation in vivo. Aim 2: To characterize the secondary costimulatory effects of Ly-6C and OX40 on IEL proliferation and cytokine activity: to determine the role of immune (CD3 signaling) vs. non-immune (IFN-alpha) induction of Ly-6C on IEL proliferative activities. Aim 3: To use small selective gene and protein array panels of T cell immunoregulatory response molecules to map the appearance of immune-activating cytokines and chemokines in lELs as they proceed from the partially activated stage into intermediated and fully activated stages. Aim 4: To use small selective gene and protein array panels of T cell immunoregulatory response molecules to identify inflammatory and immunoregulatory cytokines and chemokines in lELs from SAMP1/YitFc mice prior to and after the development of chronic small intestinal inflammation in order to identify important immunoregulatory response molecules and costimulatory signals that are linked to intestinal inflammation; to initiate intervention therapy in SAMP1/YitFc mice based on findings from studies in Specific Aims 1, 2, and 3. These studies will provide important new information about the cellular and molecular events that regulate IEL activation, and will have direct implications for understanding intestinal T cells during infection, cancer, and autoimmunity.

这是一个项目的继续，该项目的长期目标是通过表征通过激活驱动肠道上皮内淋巴细胞(LELs)的刺激和共刺激信号，在小肠上皮水平确定T细胞效应器机制。这些研究的中心假设是，小肠LELs是部分激活的T细胞，可以通过共刺激激活的有序过程快速驱动其表达额外的效应器活动，所产生的效应器反应的性质和大小是这些激活信号的直接结果。有四个综合的具体目标。目的：研究CD43 S7+和S7-LELs在细胞凋亡、趋化死亡和激活诱导的细胞死亡中的协同刺激作用，明确CD43在体内IEL增殖中的作用。目的：研究Ly-6C和OX40对IEL增殖和细胞因子活性的二次共刺激作用：确定免疫(CD3信号)和非免疫(干扰素-α)诱导对IEL增殖活性的影响。目的：利用T细胞免疫调节反应分子的小分子选择性基因和蛋白质阵列定位免疫激活细胞因子和趋化因子从部分激活阶段进入中间和完全激活阶段。目的4：利用T细胞免疫调节反应分子的小分子选择性基因和蛋白质阵列 鉴定SAMP1/YitFc小鼠LELs在慢性小肠炎发生前后的炎症和免疫调节细胞因子和趋化因子，以确定与肠道炎症相关的重要免疫调节反应分子和共刺激信号；根据特定目标1、2和3的研究结果启动对SAMP1/YitFc小鼠的干预治疗。这些研究将提供关于调节IEL激活的细胞和分子事件的重要新信息，并将对了解感染、癌症和自身免疫过程中的肠道T细胞具有直接意义。