TRANSGENIC MOUSE MODELS FOR B LYMPHOCYTE TOLERANCE AND AUTOIMMUNITY

B 淋巴细胞耐受和自身免疫的转基因小鼠模型

• 批准号: 6234675
• 负责人: CHRISTOPHER GOODNOW
• 金额: $ 13.69万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6234675
• 关键词: B cell receptor; B lymphocyte; T cell receptor; antibody formation; autoantibody; autoantigens; autoimmune disorder; flow cytometry; gene rearrangement; genetically modified animals; helper T lymphocyte; immune tolerance /unresponsiveness; immunoglobulin genes; immunoregulation; laboratory mouse; lysozyme; major histocompatibility complex; thyroid gland; thyroiditis; tissue /cell culture

Autoantibodies to a variety of self antigens are specific diagnostic markers for many autoimmune diseases, and their pathogenic role is well established in a subset of these disorders. The events underlying autoantibody production nevertheless remain obscure. Studies of B cell self-tolerance and auto immunity have been confounded by the complexity of different self antigens and the enormous variability in the frequency, affinity, and isotype of antigen-specific B cells. To circumvent these problems, a transgenic mouse model will be employed. The development of tolerance or autoimmunity to a single neo-self antigen, hen egg lysozyme, will be studied using transgenic animals that express lysozyme in different forms, levels, and tissues. In parallel, established and new lines of transgenic mice expressing rearranged immunoglobulin genes will provide a source of homogenous antigen specific B cells, expressing lysozyme-binding receptors with a distinct affinity or isotype. Lysozyme-specific helper T cells will be obtained from similar TCR gene transgenic mice. In AIMS l and 2, these animals will be used to track mechanisms for censoring self-reactive B and T cells in vivo, and define whether autoantibodies to particular classes of autoantigens result from natural limits in B and T cell censoring or by circumstances that allow self-reactive B cells to resist censoring. Transgenic animal models developed in AIMS 1 and 2 will then be used in AIM 3 to determine if additional immunoregulatory mechanisms exist to control self-reactive B and T-cells that escape censoring. Two distinct and relevant scenarios will be studied, where autoreactive B and T-cells escape censoring and can potentially initiate autoimmunity to lysozyme expressed as a cell membrane autoantigen either systemically or localized to the thyroid gland. The role of autoreactive B cells and autoantibody of different isotypes in development of systemic or thyroid pathology will be determined. These studies should provide important insights into the pathogenesis of a range of human autoimmune diseases, such as systemic lupus erythematosus and Grave's disease.

针对多种自身抗原的自身抗体是特异性诊断 许多自身免疫性疾病的标志物，它们的致病作用很好 在这些疾病的一个子集中建立。背后的事件 自身抗体的产生仍然不清楚。 B细胞自身耐受性和自身免疫性的研究受到以下因素的混淆： 不同自身抗原的复杂性和 抗原特异性B细胞的频率、亲和力和同种型。 到 为了避免这些问题，将采用转基因小鼠模型。的 母鸡对单一新自身抗原产生耐受性或自身免疫 卵溶菌酶，将使用转基因动物进行研究， 不同形式、水平和组织的溶菌酶。 与此同时， 已建立的和新的表达重排的转基因小鼠系 免疫球蛋白基因将提供同源抗原特异性的来源， B细胞，表达具有不同亲和力的溶菌酶结合受体，或 同种型 溶菌酶特异性辅助T细胞将从类似的细胞中获得。 TCR基因转基因小鼠。在AIMS 1和2中，这些动物将用于 追踪体内检查自身反应性B和T细胞的机制，和 定义是否产生针对特定类别自身抗原的自身抗体 从B和T细胞删失中的自然限制或由 允许自身反应性B细胞抵抗审查。 AIMS 1和2中开发的转基因动物模型将用于 目的3确定是否存在其他免疫调节机制， 控制逃避审查的自身反应性B和T细胞。两个不同 和相关的情况将进行研究，其中自体反应性B和T细胞 逃避审查，并可能引发对溶菌酶的自身免疫 表达为细胞膜自身抗原，或者是全身性的或者是局部的 对甲状腺的影响自身反应性B细胞和自身抗体在原发性肝癌中的作用 不同的同种型在全身或甲状腺病理的发展将是 测定 这些研究应该提供重要的见解， 一系列人类自身免疫性疾病的发病机制，如全身性 红斑狼疮和格雷夫斯病