IDDM GENES AND INTERFERON GAMMA

描述：（改编自研究者摘要）：作为 在正常的宿主防御中，CD 4 + T细胞的Th 1亚群促进炎症反应， 免疫反应，有效地消除细胞内病原体。在 胰岛素依赖型糖尿病（IDDM），IFN产生偏倚的发现 γ，由Th 1效应细胞产生的主要细胞因子，表明 自身免疫反应可能是环境或遗传编程， 对破坏性Th 1表型的抑制。分子和遗传途径， 调节Th 1或Th 2效应子亚型的进化知之甚少; 我们的研究使用转基因小鼠与报告基因控制IFN γ 启动子元件表明转录调控的进化受到严格的调控， 在T辅助细胞发育过程中控制IFN γ基因表达。的IFN γ启动子包含独立的调控元件， 响应于细胞因子信号传导（IL-12、IL-18）和T细胞受体的表达 (TCR)信号我们发现NOD CD 4 T细胞（而不是其他菌株） 响应于多克隆TCR而容易分化成Th 1亚群 在不存在IL-12的情况下刺激。这使Th 1亚群的发育发生倾斜 早于临床疾病的最早证据，与性别无关， 并被来自B6或B10菌株的抗病遗传位点逆转。 这些数据表明，NOD CD 4 T细胞的分子编程使T细胞 向独立于抗原结合的Th 1亚群发展 NOD MHC的性质和自身抗原的性质， 单个T细胞。本申请的目的是：1）确定 异常的转录或生化途径，允许NOD T细胞 经历偏斜的Th 1分化，2）确定疾病的贡献 对这种偏斜的Th 1分化的易感性/抗性基因座，3）鉴定 IFN γ启动子TCR应答元件的作用， 进化过程中IFN γ基因表达的IL-12 R/IL-18 R应答元件 和4）确定特定IDD基因座对IFN γ的贡献 从胰岛炎向糖尿病转变过程中胰岛中的启动子激活。 这些问题不仅仅是学术上的兴趣。这些问题的答案 可以使免疫反应从破坏性的Th 1细胞中“恢复”， 保护性Th 2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.