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

基本信息

批准号：
8134362
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
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-07-31
项目状态：
已结题

项目摘要

DESCRIPTION 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 self antigens, 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 ge

描述抽象的自身免疫是一种自我毁灭性的免疫疾病，通常针对特定的组织或器官。尽管疾病表现可能是组织特异性的，但它们不一定起源于该特定组织。此外，患有特定自身免疫性疾病的个体存在针对其他靶组织产生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自我耐受性崩溃引起的，其中致病性自身反应性 T 细胞是主要贡献者。 T细胞对“自身”的耐受性最初是在胸腺选择过程中在胸腺中建立的。强自身反应性 T 细胞要么被克隆删除，要么被克隆偏离，成为调节性 T 细胞，是自身攻击性免疫细胞的关键抑制剂。由于这种决定性的选择过程在自我耐受中发挥着基础作用，我们假设对自身免疫的易感性可能源于控制克隆删除与克隆偏差的中央过程的主要缺陷。该提案将检验这一假设，并最终寻求确定导致自身免疫易感性的主要缺陷和影响因素。了解缺陷是，此选择过程最终将允许及早发现患有自身免疫性疾病高风险的个体。除了检测自身免疫易感性之外，这项研究还将对预防和有效治疗自身免疫性疾病产生重要影响。虽然通过自身抗原免疫诱导抑制性调节性T细胞的产生是可行的，但有可能会产生致病性自身反应性细胞，从而加剧疾病。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，以确保有效的基因表达。