MYOCYTE RESPONSES DURING EXPERIMENTAL MYASTHENIA GRAVIS

实验性重症肌无力期间心肌细胞的反应

• 批准号: 2884219
• 负责人: KEITH A KROLICK
• 金额: $ 18.81万
• 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: 1999-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2884219
• 关键词: T lymphocyte; acetylcholine; antiantibody; antigen presentation; cell adhesion molecules; cell line; chemokine; cytokine; disease /disorder model; enzyme linked immunosorbent assay; growth factor; immunization; immunocytochemistry; immunomodulators; laboratory rat; leukocyte activation /transformation; lymph nodes; lymphocyte proliferation; major histocompatibility complex; monoclonal antibody; monocyte chemoattractant protein 1; muscle cells; myasthenia gravis; neural cell adhesion molecules; nicotinic receptors

Acetylcholine receptors (AChR) are expressed on muscle membranes and are responsible for the reception of signals from nerves that stimulate muscle contraction. Myasthenia gravis (MG) is a neuromuscular disease that is the result of impaired muscle contraction caused by autoantibodies directed at the AChR. However, circulating serum titers of anti-AChR antibodies do not correlate well with disease severity in patients with MG and this lack of correlation has led to the search for other factors which may help determine eventual disease severity. Therefore, it is our hypothesis that muscle is not a passive participant in the development of disease symptoms in MG and, in fact, plays a very important active role by producing immunomodulating factors that can influence the eventual immunopathological impact of the immune system on muscle. The experimental rat model for MG is to be used to test this hypothesis. Accordingly, Lewis rats are to be immunized with purified AChR which results in the production of anti-AChR antibodies and Experimental Autoimmune Myasthenia Gravis (EAMG). Studies will focus on the production of, and responses to, cytokines by muscle cells in rats with EAMG. In this regard, muscle cell lines will be exposed in vitro to selected cytokines in the presence or absence of anti-AChR antibodies derived from Lewis rats. The readout will be the induction of myocyte products with immunomodulating activities (i.e., cytokines, chemokines, membrane interaction molecules). Similarly, myocyte cell lines derived from a rat strain known to be resistant to the induction of EAMG (Wistar Furth) will be evaluated for differences in myocyte responses that would explain differences in disease susceptibility. Conclusions based on in vitro observations will then be verified in AChR-immunized Lewis rats during the induction phase of the immune response, as well as in rats that have received pre-formed anti-AChR antibodies known to possess differing abilities to induce disease symptoms.

乙酰胆碱受体（ACHR）在肌肉膜上表达，并负责刺激肌肉收缩的神经的信号。 肌无力重症（MG）是一种神经肌肉疾病，是由针对ACHR的自身抗体引起的肌肉收缩受损的结果。但是，抗ACHR抗体的循环血清滴度与MG患者的疾病严重程度不太相关，并且缺乏相关性导致寻找其他因素，这些因素可能有助于确定最终的疾病严重程度。 因此，我们的假设是，肌肉不是MG疾病症状发展的被动参与者，实际上，通过产生可以影响免疫系统对肌肉最终的免疫病理影响的免疫调节因素来起着非常重要的活跃作用。 MG的实验大鼠模型应用于检验该假设。 因此，刘易斯大鼠应通过纯化的ACHR进行免疫，这会导致抗ACHR抗体的产生和实验性自身免疫性肌无力肌无力重为ravis（EAMG）。研究将侧重于EAMG大鼠肌肉细胞对细胞因子的产生和反应。 在这方面，在存在或不存在源自刘易斯大鼠的抗ACHR抗体的情况下，将在体外暴露于选定的细胞因子。 读数将是具有免疫调节活性（即细胞因子，趋化因子，膜相互作用分子）的肌细胞产物的诱导。 同样，将评估从已知具有抗EAMG诱导的大鼠菌株（Wistar furth）的大鼠菌株的肌细胞细胞系，以评估肌细胞反应的差异，这可以解释疾病敏感性的差异。 然后，在免疫反应的诱导阶段以及接受预先形成的抗ACHR抗体的大鼠中，将在ACHR免疫的Lewis大鼠中验证基于体外观察结果的结论，并在ACHR免疫的刘易斯大鼠中得到验证。