IMMUNOBIOLOGY OF AUTOIMMUNITY

自身免疫的免疫生物学

• 批准号: 3407156
• 负责人: VANDA A LENNON
• 金额: $ 20.53万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1991-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3407156
• 关键词: acquired immunodeficiency; animal age group; antibody formation; antigen antibody reaction; autoantibody; autoimmune disorder; cellular immunity; complementary DNA; enzyme linked immunosorbent assay; epithelium; gene expression; human age group; human subject; humoral immunity; immunochemistry; karyotype; monoclonal antibody; muscle cells; myasthenia gravis; neoplastic cell culture for noncancer research; provirus; serology /serodiagnosis; thymus; tissue /cell culture; virus antigen

Our goal is to investigate the intrathymic genesis of autoimmunity. Specific investigations are based on a new concept of the role of the thymus in at least one form of autoimmunity, the neuromuscular disease myasthenia gravis (MG). Most thymic epithelial cells express Ia constitutively, and medullary epithelial cells express nicotinic acetylcholine receptors (AChR), the antigen of MG. Much is known about the role of anti-AChR autoantibodies in causing failure of neuromuscular transmission in MG, but nothing is known about why these antibodies arise. In MG the thymus is a major site of anti-AChR antibody production. Its removal frequently is followed by remission of the disease. The thymus undergoes neoplastic transformation in 15% of MG patients. Studies outlined in this proposal concern the role of thymic epithelial cells in initiating autoimmunity to AChR. Hypotheses to be tested are that: i) AChR associated with thymic epithelial cells is the primary immunogen of spontaneously acquired MG; ii) this immunogenicity is promoted by activation of vertically transmitted proviral genes; iii) production of anti-AChR autoantibodies reflects an anti-tumor/virus immune response that is progressing in situ in the thymus; iv) some epitopes of the AChR expressed on thymic epithelial cells are neuroectoderm-specific and are expressed selectively on cranial (oculobulbar) muscles. The long-term goal is to find a basis for new and more effective methods of treating MG. Materials to be tested include normal thymus tissues from mice, rats and humans, and cryopreserved thymus tissue and thymomas from MG patients. The AKR/J strain of mouse, which has a 90% incidence of thymic tumors and a paradoxical susceptibility to experimental autoimmune MG (EAMG), will be investigated as a novel model of the relationship between thymoma and MG. Methods include culture of thymic epithelial cells and thymomas, probing immunologically and with 32P-cDNA for coexpression of AChR and viral or onc gene products, generation of T cell clones, testing ability of thymic epithelial cells to present AChR, testing EAMG susceptibility in AKR/J mice with thymoma suppressed by neonatal treatment with anti-gp70 antibodies, serologic comparisons of the antigenicity of AChR in thymus and cranial and limb muscles.

我们的目标是研究胸前的起源 自身免疫性。 具体调查是基于新的 胸体在至少一种形式中的作用的概念 自身免疫性，神经肌肉疾病肌无力 （mg）。 大多数胸腺上皮细胞组成型， 和髓质上皮细胞表达烟碱乙酰胆碱 受体（ACHR），Mg的抗原。 关于 抗ACHR自身抗体在导致失败的作用 MG中的神经肌肉传播，但对 为什么这些抗体会产生。 在mg中，胸腺是主要部位 抗ACHR抗体的产生。 它的删除经常是 其次是缓解疾病。 胸腺经历 15％的MG患者的肿瘤转化。 研究 在该提案中概述了胸中上皮的作用 细胞引发自身免疫到ACHR。 要测试的假设是：i）与 胸腺上皮细胞是 自发获得毫克； ii）促进了这种免疫原性 通过激活垂直传播的病毒基因； iii） 抗ACHR自身抗体的产生反映了 抗肿瘤/病毒免疫反应在原位进展 百里香; iv）在胸腺上表达的ACHR的一些表位 上皮细胞是神经外胚层特异性的，并表达 有选择地在颅（Oculobulbar）肌肉上。 长期 目标是找到新的，更有效的方法的基础 治疗毫克。 要测试的材料包括正常胸腺 小鼠，大鼠和人类的组织以及冷冻保存的胸腺 来自MG患者的组织和胸腺瘤。 AKR/J菌株 小鼠，胸腺肿瘤的发生率为90％ 对实验性自身免疫MG的矛盾敏感性 （EAMG）将被研究为一种新型模型 胸腺瘤和MG之间的关系。 方法包括文化 胸腺上皮细胞和胸腺瘤的探测 免疫学和32p-cDNA用于ACHR的共表达和 病毒或ONC基因产物，T细胞克隆的产生， 胸腺上皮细胞的测试能力呈现ACHR， 用胸腺瘤测试AKR/J小鼠的EAMG敏感性 被抗GP70抗体的新生儿治疗抑制， 胸腺ACHR抗原性的血清学比较和 颅和肢体肌肉。