DETERMINANTS OF DISEASE IN EXPERIMENTAL MYASTHENIA GRAVI

实验性重症肌无力的疾病决定因素

• 批准号: 2039031
• 负责人: KEITH A KROLICK
• 金额: $ 17.47万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2039031
• 关键词: B lymphocyte; acetylcholine; antibody titering; antiidiotype antibody; antireceptor antibody; autoantibody; cell population study; cholinergic agents; disease /disorder model; genetic strain; helper T lymphocyte; immunoglobulin idiotypes; immunopathology; immunopathology diagnosis; isoelectric point; laboratory rat; myasthenia gravis; pathologic process

DESCRIPTION: (Applicant's abstract): Experimental autoimmune myasthenia gravis (EAmyasthenia gravis) in Lewis rats involves a neuromuscular impairment caused by a T cell dependent antibody response against the post-junctional acetylcholine receptor (AChR). The result is weakness and rapid onset fatigue in the rats very similar to AChR symptoms observed in human patients with myasthenia gravis (myasthenia gravis). However, although anti-AChR antibodies appear to be the direct cause of neuromuscular dysfunction in human patients, it has been observed that there is a disturbing lack of correlation between the titer of circulating antibody and the severity of symptoms demonstrated. Thus, in order to identify more useful relationships between anti-AChR antibody and disease, the overall goal of the proposed study is to define, in the EAmyasthenia gravis model system, those parameters that dictate when autoimmunity translates into pathology. Advantage will be taken of two rat strains that appear to mimic the human scenario in which high antibody titer in one individual translates into severe disease, while high antibody titer in another individual translates into mild or no disease. In other words, the principal investigator intends to ask why, even though both Lewis and Wistar Furth rat strains are equally efficient at producing such antibodies, is disease susceptibility observed on the one hand (in Lewis rats) and disease-resistance observed on the other hand (in Wistar Furth rats). The basic premise of this research proposal is that some, but not all, anti-AChR antibodies can cause disease (perhaps related to differences of the exact binding specificity of the antibodies produced). Therefore, the primary goal of the proposed study is to develop means by which past observations made by the principal investigator's laboratory can be clarified indicating that disease severity in EAmyasthenia gravis in Lewis rats is directly determined by the responsiveness of a small subset of the total population of AChR-responsive B cells. Thus far, the disease-causing subset of rat B cells has been found to be associated, at least in part, with an idiotypic determinant recognized by a monoclonal anti-Id antibody (11E10) recently prepared in this laboratory. Identifying and characterizing 1) specific clonotypic/idiotypic subsets of anti-AChR antibody that are most directly responsible for inducing disease symptoms in EAmyasthenia gravis and 2) the influence of immunodominant subsets of regulating helper T cells may point to more direct strategies for diagnosing and monitoring disease in humans, and may also provide new, more selective, targets for future immunotherapies.

描述：（申请人的摘要）：实验性自身免疫性肌无力 刘易斯大鼠中的raver（eamyasthenia gravis）涉及神经肌肉 由T细胞依赖性抗体反应引起的损伤 乙酰胆碱受体（ACHR）。 结果是软弱和 大鼠的快速发作疲劳与观察到的ACHR症状非常相似 肌无力重症的人类患者（肌无力）。 然而， 尽管抗ACHR抗体似乎是神经肌肉的直接原因 人类患者功能障碍，已经观察到有一个 循环抗体的滴度和 表现出症状的严重程度。 因此，为了确定更多 抗ACHR抗体与疾病之间的有用关系，总体 拟议的研究的目标是在eamyasthenia gravis模型中定义 系统，那些决定自动免疫何时转化为 病理。 将对似乎模仿的两种老鼠菌株获取优势 人类场景中高抗体滴度在一个个体中翻译 患有严重疾病，而另一个个体中的高抗体滴度 转化为轻度或没有疾病。 换句话说，校长 调查人员打算问为什么，即使刘易斯和韦斯塔尔 菌株在产生此类抗体方面同样有效，是疾病 一方面观察到的敏感性（在刘易斯大鼠）和 另一方面，（在Wistar furth大鼠中）观察到抗病性。 这 这项研究建议的基本前提是，有些但不是全部，反对 抗体会引起疾病（可能与确切的差异有关 产生的抗体的结合特异性）。 因此，主要 拟议的研究的目标是发展过去观察的手段 可以阐明由主要研究者实验室制造的 刘易斯大鼠的Eamyasthenia Gravis中的疾病严重程度直接 由一小部分总人口的响应能力决定 ACHR响应B细胞的。 到目前为止，大鼠B的致病子集 已经发现细胞至少部分与白痴相关 通过单克隆抗ID抗体（11E10）识​​别的决定因素 在这个实验室准备。 识别和表征1）具体 最直接的抗ACHR抗体的clonotypic/白痴型子集 负责诱导埃米亚斯氏菌的疾病症状和2） 调节辅助辅助T细胞的免疫主导子集的影响可能指向 为了诊断和监测人类疾病的更直接策略， 并可能为未来提供新的，更具选择性的目标 免疫疗法。