IDDM GENES AND INTERFERON GAMMA

描述：(改编自调查员摘要)：作为 正常的宿主防御，CD4+T细胞的Th1亚群促进炎症 有效消除细胞内病原体的免疫反应。在……里面 胰岛素依赖型糖尿病(IDDM)--干扰素产生偏向的发现 Th1效应细胞产生的主要细胞因子伽马提示， 自身免疫反应可能是环境或遗传编程的 分化为破坏性的Th1表型。分子和遗传途径 调节Th1或Th2效应器亚型的进化机制知之甚少； 我们使用由干扰素-γ控制的报告基因转基因小鼠的研究 启动子元件表明转录的进化受到严格的调控 辅助性T细胞发育过程中干扰素-γ基因表达的调控干扰素 伽马启动子包含单独的调控元件，这些元件控制基因 细胞因子信号转导(IL-12、IL-18)和T细胞受体的表达 (TCR)信令。我们已经发现NOD CD4T细胞(但不是其他菌株) 容易分化为Th1亚群以响应多克隆TCR 在没有IL-12的情况下进行刺激。这种偏向于Th1子集的发展 先于临床疾病的最早证据，与性别无关， 并被来自B6或B10品系的抗病基因座逆转。 这些数据表明，NOD CD4T细胞的分子编程扭曲了T细胞 不依赖抗原结合的Th1亚群的研究进展 NOD MHC的性质和所识别的自身抗原的性质 单个T细胞。本应用程序的目标是1)识别 异常转录或生化途径，允许NOD T细胞 经历倾斜的Th1分化，2)确定疾病的贡献 对这种倾斜的Th1分化的易感/抗性基因座，3)识别 干扰素-γ启动子TCR-反应元件和 IL-L2R/IL-18R-干扰素-γ基因表达的进化反应元件 以及4)确定特定的IDD基因座对干扰素-γ的贡献 从胰岛炎向糖尿病转变过程中胰岛启动子的激活。 这些问题不仅仅是学术上的兴趣。这些问题的答案 可能会使破坏性Th1的免疫反应重新两极化成为可能 表型转变为保护性Th2表型。

DESCRIPTION: (Adapted from the Investigator's abstract): As a component of normal host defense, the Th1 subset of CD4+ T cells promotes inflammatory immune responses that effectively eliminate intracellular pathogens. In insulin-dependent diabetes (IDDM), the finding of biased production of IFN gamma, the principal cytokine produced by Th1 effector cells, suggests that the autoimmune response may be environmentally or genetically programmed to polarize to a destructive Th1 phenotype. The molecular and genetic paths that regulate the evolution of Th1 or Th2 effector subtypes are poorly understood; our studies using transgenic mice with reporter genes controlled by IFN gamma promoter elements indicate a tightly regulated evolution of transcriptional control of IFN gamma gene expression during T helper cell development. The IFN gamma promoter contains separate regulatory elements, which govern gene expression in response to cytokine signaling (IL-12, IL-18) and T cell receptor (TCR) signaling. We have found that NOD CD4 T cells (but not other strains) readily differentiate into the Th1 subset in response to a polyclonal TCR stimulus in the absence of IL-12. This skewed development into the Th1 subset precedes the earliest evidence of clinical disease, is independent of gender, and is reversed by disease resistance genetic loci from the B6 or B10 strain. These data argue that the molecular programming of NOD CD4 T cells skews T cell development towards the Th1 subset independent of the antigen binding properties of the NOD MHC and the nature of the autoantigen recognized by individual T cells. The objectives of this application are to 1) identify aberrant transcriptional or biochemical paths which permit NOD T cells to undergo skewed Th1 differentiation, 2) identify the contribution of disease susceptibility/resistance loci to this skewed Th1 differentiation, 3) identify the contribution of IFN gamma promoter TCR-response elements and IL-l2R/IL-18R-response elements to IFN gamma gene expression during evolution of diabetes, and 4) identify contributions of specific IDD loci to IFN gamma promoter activation in islets during transitions from insulitis to diabetes. These questions are not simply of academic interest. Answers to these questions may make it possible to "re-polarize" immune responses from a destructive Th1 phenotype to a protective Th2 phenotype.