GENETIC-VIRAL-IMMUNOLOGIC STUDIES IN NEW ZEALAND MICE

新西兰小鼠的遗传病毒免疫学研究

• 批准号: 3169909
• 负责人: SYAMAL K DATTA
• 金额: $ 30.45万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-07-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3169909
• 关键词: B cell receptor; B lymphocyte; T cell receptor; T lymphocyte; anergy; antinuclear autoantibody; autoantibody; autoimmune disorder; clone cells; disease /disorder model; gene expression; gene mutation; genetically modified animals; hybridomas; immune tolerance /unresponsiveness; immunogenetics; immunoglobulin idiotypes; immunoglobulin structure; laboratory mouse; leukocyte activation /transformation; lymphoma; molecular pathology; neoplasm /cancer genetics; northern blottings; nucleic acid sequence; oncogenes; protein sequence; synthetic peptide; systemic lupus erythematosus; tissue /cell culture

Our long-term goal is to define the fundamental mechanism of the systemic autoimmune disease (SLE) and malignant B cell lymphomas that develop spontaneously in the crosses between NZB and the normal SWR mouse strains. The etiologic mechanism of Systemic lupus erythematosus (SLE) remains elusive because the primary antigen that triggers the pathogenic autoimmune response in this disease is unknown. In spite of this obstacle, we have cloned the select T and B cells that are pathogenic in SLE. Analyses of the structure and specificities of the receptors expressed by these particular T and B cells that are representative of the disease and studies of their regulation may lead to an understanding of the etiologic mechanism of lupus. The major goals of this application involve: 1) Pathogenic B Cells: (a) Define the structural basis of cationic charge, antigenic specificities, idiotypic cross reactions and clonal relationships among pathogenic anti-DNA autoantibodies. b) Study the germline V gene repertoire that generates the pathogenic autoantibodies, define the natural specificities of antibodies encoded by these germ line V genes and determine the degree of somatic mutations required to generate the pathogenic autoantibodies. c) Determine if the lupus-prone mice have an intrinsic B cell defect in tolerance induction or in Ig somatic mutation mechanisms using transgenic mice carrying autoantibody V genes. 2) Pathogenic T Cells: (a) Determine the V region sequences of the receptors (TCRs) expressed by the pathogenic autoantibody-inducing T cells to detect any clonal restriction/recurrent usage or any special feature in their junctional region (CDR3) sequences that would provide clues for their antigenic specificities. b) Determine the specificities of these T helper cells that preferentially interact with the pathogenic autoantibody-producing B cells, using synthetic peptides and B-B hybridomas. c) Attempt to block the pathogenic autoimmune response in vivo by rendering the autoimmune T helper cells anergic. These studies will help us to design specific therapies that could intervene in the basic steps leading to systematic autoimmune disease in lupus and may direct similar approaches for other rheumatic diseases where the inciting antigen is unknown. Furthermore, understanding the nature of the intrinsic B cell abnormally in these NZB crosses could help elucidate the mechanism of B cell lymphoma development in these mice.

我们的长期目标是确定系统的基本机制， 自身免疫性疾病（SLE）和恶性B细胞淋巴瘤， 在NZB和正常SWR小鼠品系之间的杂交中自发地产生。 系统性红斑狼疮（SLE）的发病机制仍然是 因为引发致病性自身免疫的主要抗原 这种疾病的反应是未知的。 尽管有这个障碍，我们还是 克隆了在SLE中致病的选择性T和B细胞。 分析 这些受体表达的结构和特异性 特定的T和B细胞是疾病和研究的代表 它们的调节可能导致对病因机制的理解， 狼疮 该应用程序的主要目标包括： 1)致病性B细胞：（a）定义阳离子电荷的结构基础， 抗原特异性、独特型交叉反应和克隆关系 病原性抗DNA自身抗体 B）研究产生致病性病毒的生殖系V基因库。 自身抗体，定义抗体编码的天然特异性， 这些生殖系V基因并决定体细胞突变的程度 产生致病性自身抗体所必需的。 c）确定狼疮易感小鼠是否存在内在的B细胞缺陷 耐受性诱导或在IG体细胞突变机制中使用转基因 携带自身抗体V基因的小鼠。 2)病原性T细胞：（a）确定病原性T细胞的V区序列。 由致病性自身抗体诱导T细胞表达的TCR 检测任何克隆限制/复发使用或任何特殊功能， 它们的连接区（CDR3）序列，这将为它们的 抗原特异性 B）确定这些T辅助细胞的特异性， 与产生致病性自身抗体的B细胞相互作用， 合成肽和B-B杂交瘤。 c）试图通过以下方式阻断体内致病性自身免疫应答： 使自身免疫性T辅助细胞无反应性。 这些研究将帮助我们设计特定的治疗方法， 干预导致系统性自身免疫性疾病的基本步骤， 狼疮，并可能指导其他风湿性疾病的类似方法， 激发抗原未知。 此外，了解 这些NZ B杂交中固有B细胞异常有助于阐明 这些小鼠中B细胞淋巴瘤发展的机制。