TH1 AND TH2 RESPONSES AND MYASTHENIA GRAVIS

TH1 和 TH2 反应与重症肌无力

• 批准号: 6510834
• 负责人: ANTHONY J INFANTE
• 金额: $ 29.53万
• 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/6510834
• 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：（根据研究者的摘要改编）：实验性自动免疫 肌无力的肌无力（EAMG）在敏感的小鼠中诱导 用乙酰胆碱受体（ACHR）免疫。肌肉无力被认为是 完全由高亲和力IgG自身抗体介导，很少 来自细胞介导的效应器机制的参与。最近，有力的证据 已经提供EAMG取决于Th1细胞因子的产生， 特别是IL-12和干扰素 - 伽马（IFN-GAMMA）。 IFN-Gamma已显示为 对文化中的肌肉细胞有强大的直接影响，其中 MHC II类和细胞粘附分子的上调。申请人 提出Th1细胞因子（主要是IFN-Gamma）对 体内肌肉，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 建议检验这一假设。在AIM 1中，调查人员将定义 通过给药，键Th1和Th2细胞因子在EAMG中的作用 细胞因子，单克隆抗体（mAb）对细胞因子活性中和 以及细胞因子基因基因敲除小鼠的研究。调查员将 对Th1和Th2细胞因子是拮抗或 协同作用。在AIM 2中，申请人将净化抗体 各种细胞因子的影响并通过收养评估其致病性 转移。细胞因子的直接作用将被单独测量 组合，有或没有自身抗体在肌肉细胞上的共同应用 在文化中生长。这些培养的​​肌肉细胞中的这些变化将是 与体内的肌肉组织发现相关。在AIM 3中，占主导地位 在组织特异性启动子的控制下，IFN-GAMMA受体转基因 将用于赋予IFN-gamma作用的特定组织耐药性。 该假设可能表明肌肉对IFN-Gamma的反应无反应性 对EAMG的抗性。除了在 了解MG的免疫致病基础，这种结果也可能导致 进行新的疗法。