TOLERANCE TO EXTRA-THYMIC ANTIGENS

对胸腺外抗原的耐受性

• 批准号: 2064960
• 负责人: JACQUES F MILLER
• 金额: $ 9.93万
• 依托单位: WALTER AND ELIZA HALL INST MEDICAL RES
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2064960
• 关键词: MHC class I antigen; T cell receptor; T lymphocyte; autoimmune disorder; autoimmunity; bioassay; cellular immunity; genetically modified animals; immune tolerance /unresponsiveness; interleukin 2; isoantigen; laboratory mouse; thymus; transfection

One of the central issues in immunology concerns the way in which the immune system is able to discriminate between self and non-self molecules, so that an immune response may be mounted to foreign pathogens while the body's own constituents are tolerated. This ability is, however, impaired in some patients and this results in autoimmune diseases in which the patients' own tissues are damaged by their immune system. A better understanding of the mechanisms of tolerance is required to further the basic knowledge of the immune system and to develop insights into how tolerogenic mechanisms break down, leading to a variety of autoimmune conditions. The most important cell type upon which tolerance must be imposed is the T lymphocyte which matures in the thymus. Recently, the way in Which T cells become tolerant to the antigens present in the thymus has been characterized, but it is not clear how responses to extra-thymic molecules are avoided. Therefore, the primary aim of this proposal is to investigate the mechanisms by which tolerance to self molecules not expressed in the thymus is imposed and maintained. In order to investigate these processes, transgenic mouse models will be used which produce in defined extrathymic sites antigens and antigenic peptides that have known structures and which can be seen by monoclonal antibodies. Other transgenic mice will be obtained in which the majority of T cells express receptors that are specific for the antigens used and that can be detected by appropriate monoclonal antibodies. The activity, phenotype and fate of the specific T cells will be determined in double transgenic offspring of matings between these two sets of transgenic mice and the conditions favoring autoimmunity or tolerance will be established. The effect of various antigenic peptides on T cell responsiveness will be studied with a view to blocking in vivo responses. This knowledge may lead to new methods of therapy and prevention of autoimmune diseases. It may also help devise strategies for boosting weak immune responses, and therapeutic immunotherapies directed against antigens encoded in defined tissues by oncogenes.

免疫学的核心问题之一是涉及 免疫系统能够区分自我和非自我分子， 因此，可以将免疫反应安装到外来病原体上 身体的成分被容忍。但是，这种能力受损 在某些患者中，这会导致自身免疫性疾病 患者自己的组织受到免疫系统的破坏。更好 需要了解耐受性机制才能进一步 免疫系统的基础知识，并洞悉如何 耐受性机制分解，导致多种自身免疫性 状况。 必须施加公差的最重要的细胞类型是 T淋巴细胞在胸腺中成熟。最近，T的方式 细胞变得对胸腺中存在的抗原的耐受已经 表征了，但尚不清楚如何反应对胸外分子 避免。因此，该提议的主要目的是调查 对自我分子的耐受性未表达的机制 胸腺被施加和维护。为了调查这些过程， 将使用在定义的外肌中产生的转基因小鼠模型 位点抗原和具有已知结构的抗原肽 可以通过单克隆抗体看到。其他转基因小鼠将是 获得大多数T细胞表达的受体 特定于所用抗原，可以通过适当检测到 单克隆抗体。特定T的活性，表型和命运 细胞将以双重转基因后代的分子为单位确定 这两组转基因小鼠和有利于自身免疫性的条件 或将建立公差。各种抗原肽的作用 将研究T细胞响应能力，以阻止体内 回答。 这些知识可能会导致新的治疗方法和预防方法 自身免疫性疾病。它也可能有助于制定促进弱的策略 免疫反应和针对针对的治疗性免疫疗法 通过癌基因在定义的组织中编码的抗原。