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：（改编自研究者的摘要）：实验性自身免疫 重症肌无力（EAMG）是在易感品系小鼠中诱导的 乙酰胆碱受体（AchR）免疫。肌肉无力被认为 完全由高亲和力 IgG 自身抗体介导，几乎没有 细胞介导的效应机制的参与。近日，有力证据 假设 EAMG 依赖于 Th1 细胞因子的产生， 尤其是 IL-12 和干扰素-γ (IFN-gamma)。 IFN-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 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。在目标 1 中，研究者将定义 关键 Th1 和 Th2 细胞因子在 EAMG 中的作用，通过施用重组 细胞因子，通过单克隆抗体 (mAb) 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 特别感兴趣的是 Th1 和 Th2 细胞因子是否是拮抗的或 协同作用。在目标 2 中，申请人将纯化根据 各种细胞因子的影响并通过过继评估其致病性 转移。细胞因子的直接影响将单独测量 联合应用或不联合应用自身抗体至肌肉细胞 在文化中成长。培养的肌肉细胞中的这些变化将被 与体内肌肉组织的发现相关。在目标 3 中，显性负 组织特异性启动子控制下的 IFN-γ 受体转基因 将用于赋予组织对 IFN-γ 作用的特定抵抗力。 这一假设可能表明，肌肉对 IFN-γ 的无反应可能会导致 对 EAMG 的抵抗力。除了在以下方面提供重大进步之外 了解 MG 的免疫致病基础，这样的结果也可能导致 到新颖的疗法。