GUT-DERIVED IMMUNE EFFECTOR CELLS

肠道来源的免疫效应细胞

• 批准号: 7009945
• 负责人: JOHN R KLEIN
• 金额: $ 23.84万
• 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/7009945
• 关键词: CD3 molecule; CD43 molecule; T cell receptor; T lymphocyte; apoptosis; autoimmune disorder; biological signal transduction; cell differentiation; cell proliferation; cytokine; enteritis; gastrointestinal epithelium; genetically modified animals; gut associated lymphoid tissue; immunoregulation; immunotherapy; interferon gamma; laboratory mouse; leukocyte activation /transformation; microarray technology; mucosal immunity; nonhuman therapy evaluation; passive immunization; therapy design /development

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.

这是一个项目的延续，其长期目标是通过表征通过激活驱动肠上皮内淋巴细胞（IEL）的刺激和共刺激信号，在小肠上皮水平上定义T细胞效应机制。这些研究的中心假设是小肠IEL是部分活化的T细胞，其可以通过有序的共刺激活化过程被快速驱动以表达额外的效应子活性，并且所产生的效应子应答的性质和幅度是这些活化信号的直接结果。有四个具体目标。目标1：表征CD 43 S7+和S7-lEL在细胞凋亡、死亡倾向和活化诱导的细胞死亡方面的共刺激作用;确定CD 43在体内IEL增殖中的作用。目标二：表征Ly-6C和OX 40对IEL增殖和细胞因子活性的次级共刺激作用：确定Ly-6C的免疫（CD 3信号传导）与非免疫（IFN-α）诱导对IEL增殖活性的作用。目标三：使用T细胞免疫调节反应分子的小选择性基因和蛋白质阵列面板来绘制lEL中免疫活化细胞因子和趋化因子的外观，因为它们从部分活化阶段进入中间和完全活化阶段。目的4：利用T细胞免疫调节分子的小选择性基因和蛋白质阵列板， 鉴定慢性小肠炎症发生前后SAMP 1/YitFc小鼠lEL中的炎性和免疫调节细胞因子和趋化因子，以鉴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中的研究结果，在SAMP 1/YitFc小鼠中启动干预治疗。这些研究将提供有关调节IEL激活的细胞和分子事件的重要新信息，并将对理解感染，癌症和自身免疫期间的肠道T细胞产生直接影响。