IMMUNE MECHANISMS IN THE INDUCTION OF MURINE MYASTHENIA

诱发小鼠肌无力的免疫机制

基本信息

批准号：
3407164
负责人：
ANDREW R PACHNER
金额：
$ 10.46万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-09-01 至 1990-03-31
项目状态：
已结题

项目摘要

Myasthenia gravis(MG) and its experimental models have become important diseases for the study of autoimmunity because the autoantigen, the nicotinic acetylcholine receptor(AChR), is a purified and well-characterized protein. This proposal addresses the problems of induction and propagation of autoimmunity in myasthenia; very little is known now about these topics in MG or any other autoimmune disease. There are two major thrusts, each dealing with a concept--the idiotype network and immunoregulation--central to the understanding of autoimmunity. The first deals with the initiation of anti-AChR autoimmunity and a unique, myasthenia-like disease in mice and rabbits via "internal images" within the idiotype network. Our use of monoclonal antibodies directed against AChR ligands, as well as synthetic peptides of the AChR-binding portion of snake toxins and rabies virus, will considerably facilitate extension of our preliminary work. The second thrust is the elucidation of the mechanisms by which immunoregulatory mechanisms are bypassed and clinical weakness propagated in the mouse model of myasthenia. Our preliminary work has shown that the disease we have induced using the anti-neurotoxin antiboides, network-induced myasthenic syndrome (NIMS), resembles experimental myasthenia in a number of ways: normal animals after immunization develop fatigable weakness reversed by Tensilon, anti-AChR antibodies appear, and electromyography using repetitive nerve stimulation reveals myasthenic features. Our generation of monoclonal antibodies directed against AChR ligands and their synthetic peptides will allow the use of a highly purified "internal image" as immunogens. As in our previous studies "internal image" -immunized animals will be analyzed clinically, serologically, electromyographically, and pharmacologically. This information will predict the nature of the "internal image" that is most likely to generate clinical disease, as well as providing information about the functional significance of various forms of "internal image". Finally, sera from patients with myasthenia gravis and Lambert-Eaton syndrome will be tested for their ability to interact with the various "internal images" of AChR. We have found that in both NIMS and murine experimental myasthenia (EAMG) only a minority of immunized mice manifest clinical weakness despite evidence for subclinical disease in all mice. Although the current dogma is that the reason for this is that mice have a high "safety factor" of neuromuscular transmission, we feel that the lack of clinical weakness may be due to highly efficient immunoregulation in these animals that may diminish the strength, i.e. pathogenicity, of the autoimmune response. We plan to investigate this question by interfering with immune suppression using irradiation, cyclophosphamide, contrasuppression, monoclonal antibodies against suppressor cells and their factors, mouse strains having putative suppressor cell defects, and estrogen. We will also assess by transfer experiments whether depletion of suppresor cells or amplification of the helper T cell population will increase the frequency and severity of disease.

肌无力重症（MG）及其实验模型已成为自身免疫研究的重要疾病，因为自动抗原，烟碱乙酰胆碱受体（ACHR），是一个纯化且特征良好的蛋白质。该提案解决了自身免疫的归纳和传播的问题肌无力现在，关于这些主题在mg或任何其他自身免疫性疾病。有两个主要推力，每个都涉及一个概念 - 愚蠢的网络和免疫调节 - 中心理解自身免疫性。第一个涉及抗ACACHR自身免疫的启动通过小鼠和兔子的独特的肌无损的疾病白痴网络中的“内部图像”。我们的使用针对ACHR配体的单克隆抗体以及蛇毒素ACHR结合部分的合成肽狂犬病病毒将大大促进我们的扩展初步工作。第二个推力是阐明绕过免疫调节机制的机制和在小鼠模型中传播的临床无力肌无力。我们的初步工作表明我们诱发的疾病使用抗神经毒素抗体，网络诱导的肌无力综合征（NIMS），类似于实验性肌无力方式：免疫后的正常动物发育疲劳 tensilon逆转无力，抗ACHR抗体出现，并且使用重复性神经刺激的肌电图显示肌关系特征。我们一代的单克隆抗体针对ACHR配体及其合成肽的针对允许将高度纯化的“内部图像”作为免疫原子。就像我们以前的研究“内部图像”免疫动物将在临床，血清学，肌电图上进行分析，和药理学。此信息将预测性质最有可能生成临床的“内部图像” 疾病，并提供有关功能的信息各种形式的“内部图像”的意义。最后，血清来自肌无力的重症患者和兰伯特·埃顿综合征将对它们与该综合的能力进行测试 ACHR的各种“内部图像”。我们发现在NIM和鼠实验中都肌无力（EAMG）只有少数免疫小鼠表现出来临床弱点，尽管有证据表明所有亚临床疾病老鼠。尽管目前的教条是原因是小鼠具有高度“安全系数”的神经肌肉传播，我们认为缺乏临床弱点可能是由于这些动物的高效免疫调节，可能会降低自身免疫的强度，即致病性回复。我们计划通过干扰使用辐照，环磷酰胺，免疫抑制，抗抑制，对抑制细胞的单克隆抗体以及它们的因素，具有假定抑制细胞的小鼠菌株缺陷和雌激素。我们还将通过转移评估实验是消耗抑制细胞还是扩增辅助T细胞群体的频率将增加频率和疾病的严重程度。