TH1 AND TH2 RESPONSES AND MYASTHENIA GRAVIS

TH1 和 TH2 反应与重症肌无力

• 批准号: 6170714
• 负责人: ANTHONY J INFANTE
• 金额: $ 27.84万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170714
• 关键词: autoantibody; cholinergic receptors; cytokine receptors; disease /disorder model; genetic promoter element; genetically modified animals; interferon gamma; interleukin 12; interleukin 4; laboratory mouse; leukocytes; monoclonal antibody; muscle cells; myasthenia gravis; neutralizing antibody; passive immunization; recombinant proteins

DESCRIPTION: (Adapted from Investigator's abstract): Experimental autoimmune myasthenia gravis (EAMG) is induced in susceptible strains of mice by immunization with acetylcholine receptor (AchR). Muscle weakness is thought to be entirely mediated by high-affinity IgG autoantibodies, with little participation from cell-mediated effector mechanisms. Recently, strong evidence has been provided that EAMG depends on the production of Th1 cytokines, especially IL-12 and interferon-gamma (IFN-gamma). IFN-gamma has been shown to have powerful direct influences on muscle cells in culture, among them upregulation of MHC class II and cell adhesion molecules. The applicant proposes that Th1 cytokines, predominantly IFN-gamma, have a direct action on muscle in vivo, causing increased susceptibility to immune-mediated damage and interference with muscle function, regeneration and repair. Three specific aims are proposed to test this hypothesis. In Aim 1, the investigator will define the role of key Th1 and Th2 cytokines in EAMG, by administration of recombinant cytokines, neutralization of cytokine activity by monoclonal antibodies (mAbs) and studies in cytokine gene knockout mice. The investigator will be particularly interested in whether Th1 and Th2 cytokines are antagonistic or synergistic. In Aim 2, the applicant will purify antibodies made under the influence of various cytokines and assess their pathogenicity by adoptive transfer. The direct effect of cytokines will be measured, individually and in combinations, with and without co-application of autoantibodies to muscle cells grown in culture. These changes in cultured muscle cells will then be correlated with muscle tissue findings in vivo. In Aim 3, a dominant-negative IFN-gamma receptor transgene under the control of tissue specific promoters will be used to confer specific tissue resistance to the actions of IFN-gamma. This hypothesis may show that muscle unresponsiveness to IFN-gamma may confer resistance to EAMG. In addition to providing significant advances in understanding the immunopathogenic basis of MG, such a result could also lead to novel therapy.

描述：(改编自研究人员摘要)：实验性自身免疫 重症肌无力(EAMG)在易感品系小鼠中的诱导 乙酰胆碱受体(AchR)免疫。肌肉无力被认为是 完全由高亲和力免疫球蛋白自身抗体介导，几乎没有 来自细胞介导的效应机制的参与。最近，有强有力的证据表明 已经提供了EAMG依赖于Th1细胞因子的产生， 尤其是IL-12和干扰素-γ。干扰素-γ已被证明可以 对培养中的肌肉细胞有强大的直接影响，其中 上调MHC-II类分子和细胞黏附分子。申请人 提出Th1细胞因子，主要是干扰素-γ，对 体内的肌肉，导致对免疫介导的损伤的敏感性增加 干扰肌肉功能、再生和修复。三个具体目标 来检验这一假说。在目标1中，调查员将定义 重组人Th1和Th2细胞因子在EAMG中的作用 细胞因子，单抗中和细胞因子活性 以及细胞因子基因敲除小鼠的研究。调查员将会是 特别感兴趣的是Th1和Th2细胞因子是拮抗的还是 协同效应。在目标2中，申请者将提纯根据 过继感染对多种细胞因子的影响及其致病性评价 调职。细胞因子的直接影响将被单独和间接测量。 肌肉细胞自身抗体联合应用和不联合应用的组合 在文化中成长。这些在培养的肌肉细胞中的变化将是 与活体肌肉组织的发现相关。在目标3中，一个显性否定 组织特异性启动子调控下的干扰素-γ受体转基因 将被用来赋予特定组织对干扰素-伽马作用的抵抗力。 这一假设可能表明，肌肉对干扰素-伽马的无反应性可能会导致 对EAMG的抗性。除了在以下方面提供重大进展外 了解MG的免疫致病基础，这样的结果也可能导致 为新疗法干杯。