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：（改编自研究者摘要）：实验性自身免疫性 重症肌无力（EAMG）在敏感品系的小鼠中通过以下诱导： 乙酰胆碱受体（AchR）免疫。肌肉无力被认为是 完全由高亲和力IgG自身抗体介导， 参与细胞介导的效应机制。最近，有力的证据表明， 已经提出EAMG依赖于Th 1细胞因子的产生， 特别是IL-12和干扰素-γ（IFN-γ）。IFN-γ已被证明 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Th 1细胞因子，主要是IFN-γ，对 体内肌肉，导致对免疫介导的损伤的易感性增加， 干扰肌肉功能、再生和修复。三个具体目标 来检验这一假设。在目标1中，研究者将定义 通过施用重组体，关键Th 1和Th 2细胞因子在EAMG中作用 细胞因子，通过单克隆抗体（mAb）中和细胞因子活性 和细胞因子基因敲除小鼠的研究。研究者将 特别感兴趣的是Th 1和Th 2细胞因子是拮抗的还是 协同作用。在目标2中，申请人将纯化在本发明的方法下制备的抗体。 各种细胞因子影响并评估其致病性 转移细胞因子的直接作用将单独测量，并在 联合应用和不联合应用针对肌细胞的自身抗体 在文化中成长。这些变化在培养的肌肉细胞，然后将 与体内肌肉组织发现相关。在目标3中，显性否定 在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作用的特异性抗性。 这一假设可能表明，肌肉对IFN-γ的无反应性可能导致 抗EAMG。除了在以下方面取得重大进展外， 了解MG的免疫病理基础，这样的结果也可能导致 到新疗法