Uncovering the Missing Link that Determines Susceptibility to Autoimmunity

发现决定自身免疫易感性的缺失环节

• 批准号: 8318169
• 负责人: HILDE MC CHEROUTRE
• 金额: $ 93.51万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318169
• 关键词: Antigen-Presenting Cells; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Cells; Clonal Deletion; Defect; Disease; Early Diagnosis; Generations; Hepatic Stellate Cell; Immune; Immune System Diseases; Immunization; Individual; Link; Organ; Play; Predisposition; Prevention; Process; Production; Regulatory T-Lymphocyte; Research; Risk; Role; Self Tolerance; T-Lymphocyte; Testing; Thymus Gland; Tissues; abstracting; effective therapy; high risk; novel strategies; prevent

II. Abstract: Autoimmunity is a self-destructive immune disorder and often directed towards a particular tissue or organ. Although the disease manifestations can be tissue-specific, they do not necessarily originate in that particular tissue. Furthermore, individuals with a specific autoimmune disease are at risk to develop additional autoimmunity directed towards other target tissues. What all autoimmune diseases do have in common is that they result from a breakdown in self-tolerance, with a major contribution from pathogenic self-reactive T cells. T cell tolerance towards ¿self¿ is initially established in the thymus during the process of thymic selection. Strong self-reactive T cells are either clonally deleted or alternatively clonally deviated to become regulatory T cells that are key suppressors of auto-aggressive immune cells. Since this decisive selection process plays a fundamental role in self-tolerance, we postulate that susceptibility to autoimmunity might originate from a principal defect in the central process that governs clonal deletion versus clonal deviation. The proposal will test this hypothesis and ultimately seek to identify the primary deficiency and contributing factors that underlie susceptibility to autoimmunity. Understanding the defect(s) is this selection process will ultimately allow for early detection of individuals that are at a high risk to develop autoimmune diseases. Aside from detecting autoimmune susceptibility, this research will have vital implications for the prevention and effective treatment of autoimmune diseases. Although it is feasible to induce the production of suppressive regulatory T cells through immunization with selfantigens, it is possible that pathogenic self-reactive cells will be generated, thus exacerbating the disease. Our proposed study will explore a novel strategy to prevent and/or treat autoimmunity. Hepatic stellate cells will be used as natural, regulatory, antigen-presenting cells to assure the efficient generation of regulatory T cells that may suppress pathogenic autoimmune cells and thereby control autoimmunity.

二、摘要： 自身免疫是一种自我毁灭性免疫疾病，通常针对 尽管疾病表现可能具有组织特异性，但它们确实具有组织特异性。 不一定起源于该特定组织。 自身免疫性疾病有产生针对其他疾病的额外自身免疫的风险 所有自身免疫性疾病的共同点是它们都是由靶组织引起的。 自我耐受性的崩溃，主要来自致病性自身反应性 T 细胞。 细胞对 ¿ 的耐受性自己在胸腺过程中最初在胸腺中建立 强自身反应性 T 细胞要么被克隆删除，要么被克隆选择。 变异成为调节性 T 细胞，是自身攻击性免疫的关键抑制剂 由于这种决定性的选择过程在自我耐受中发挥着重要作用，因此我们 假设对自身免疫的易感性可能源于免疫系统的主要缺陷 控制克隆删除与克隆偏差的中央过程。 该提案将测试这一假设并最终找出主要缺陷 以及导致自身免疫易感性的因素。 缺陷是这个选择过程最终将允许及早发现那些 患自身免疫性疾病的风险很高。 除了检测自身免疫易感性之外，这项研究还将具有重要意义 预防和有效治疗自身免疫性疾病虽然是可行的。 通过自身抗原免疫诱导抑制性调节性 T 细胞的产生， 可能会产生致病性自身反应细胞，从而加剧 这种疾病。 我们提出的研究将探索一种预防和/或治疗自身免疫的新策略。 肝星状细胞将被用作天然的、调节性的、抗原呈递细胞，以确保 有效生成可抑制致病性自身免疫细胞的调节性 T 细胞 从而控制自身免疫。