MOLECULAR PATHOGENESIS OF MURINE MYASTHENIA GRAVIS

鼠重症肌无力的分子发病机制

基本信息

批准号：
3405897
负责人：
PREMKUMAR CHRISTADOSS
金额：
$ 8.29万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-04-01 至 1988-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3405897
关键词：
autoimmune disorder gene complementation genetic mapping histocompatibility gene immune complex diseases immune response genes immunogenetics immunosuppression molecular pathology monoclonal antibody mutant myasthenia gravis

项目摘要

The role of HLA-DR-A and -B antigen in myasthenia gravis or other autommune disease pathogenesis is not well understood. It is possible to study the role of murine I-A, H-2K and H-2D molecules (the murine analogue of HLA molecules) in the pathogenesis of murine experimental autoimmune myasthenia gravis (EAMG). Previous studies have established the role of immune response genes in the I-A subregion on EAMG susceptibility. We propose to study the role of these molecules by determining the degree of EAMG susceptibility of the B6 I-A and H-2K locus mutant strain and by in vivo administration of anti I-A, H-2K and H-2D monoclonal antibodies (m-ab) before and after established autoimmunity to AChR. Further the generation of acetylcholine receptor specific suppressor cells in m-ab treated animals will be evaluated. We will study the cellular (T cells and/or macrophage) defect leading to low responsiveness to AChR in the I-A mutant strain bm12. Moreover, we will evaluate the role of I-A gene dose effect, 4jt gene (which controls the expression of murine T cell I-J expression), and gene complementation on EAMG pathogenesis. EAMG will be induced in B6 and B6 mutant strains by immunization with AChR in CFA. The following six critical parameters will be used in order to determine the degree of EAMG pathogenesis: (1) clinical muscle weakness, (2) electromyography, (3) AChR-specific lymphocyte proliferation, (4) autoantibody response to AChR, (5) amount of muscle AChR complexed with antibody and (6) carcass muscle AChR loss. The proposed investigations may lead to studies on the generation of AChR specific suppressor factors by AChR specific suppressor T cells and their therapeutic role in murine EAMG, and to studies on the possible immunotherapeutic role of HLA-DR antibody in human MG. Further, the proposed study might serve as a prototype for other organ specific animal and human models of autoimmune diseases where there is an H-2 or HLA linkage.

HLA-DR-A和-b抗原在肌无力的GRAVIS或其他Autommune中的作用疾病发病机理尚不清楚。可以研究鼠I-A，H-2K和H-2D分子的作用（HLA的鼠类似物分子）在鼠类实验性自身免疫性肌无力的发病机理中 GRAVIS（EAMG）。先前的研究已经确定了免疫的作用 I-A子区域的响应基因在EAMG易感性上。我们建议通过确定EAMG的程度来研究这些分子的作用 B6 I-A和H-2K基因座突变体菌株的敏感性和体内抗I-A，H-2K和H-2D单克隆抗体（M-AB）的给药建立自身免疫之前和之后。进一步的一代 M-AB处理的动物中的乙酰胆碱受体特异性抑制细胞将进行评估。我们将研究细胞（T细胞和/或巨噬细胞）缺陷导致I-A突变株中对ACHR的响应性较低 BM12。此外，我们将评估I-A基因剂量效应的作用，4JT 基因（控制鼠T细胞I-J表达的表达）和 EAMG发病机理上的基因互补。 EAMG将在B6中诱导，并且 B6突变菌株通过CFA中的ACHR免疫。以下六个关键参数将用于确定EAMG的程度发病机理：（1）临床肌肉无力，（2）肌电图，（3） ACHR特异性淋巴细胞增殖，（4）对ACHR的自身抗体反应，（5）与抗体和（6）car体肌肉复合的肌肉量 ACHR损失。拟议的研究可能导致对ACHR产生的研究通过ACHR特异性抑制剂T细胞及其其特异性抑制因子在鼠EAMG中的治疗作用，并研究可能 HLA-DR抗体在人Mg中的免疫治疗作用。此外，拟议的研究可能是其他特定器官动物的原型以及患有H-2或HLA的自身免疫性疾病的人类模型连锁。