Functions of Hopx in immune tolerance in a model of Multiple Sclerosis

Hopx 在多发性硬化症模型免疫耐受中的作用

• 批准号: 8845513
• 负责人: Daniel Hawiger
• 金额: $ 37.66万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-05 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8845513
• 关键词: Acute; Area; Autoimmune Diseases; Autoimmune Process; Autoimmunity; CD44 gene; Cell physiology; Cells; Dendritic Cells; Disease; Encephalomyelitis; FOS gene; Foundations; Generations; Genes; Genetic Transcription; Goals; Health; IL2RA gene; Immune; Immune Tolerance; Immunity; Immunosuppression; Immunotherapy; Inflammatory; Interleukin-2; Investigation; JUN gene; Link; Lymphocyte; Mediating; Modeling; Molecular; Molecular Target; Multiple Sclerosis; Pathway interactions; Peripheral; Process; Proteins; Regulation; Regulatory T-Lymphocyte; Role; Serum Response Factor; Signal Transduction; T-Lymphocyte; anergy; autoreactive T cell; homeodomain; mouse model; novel; research study

DESCRIPTION (provided by applicant): A breakdown of immune tolerance and the generation of pro-inflammatory lymphocytes cause autoimmune diseases, including Multiple Sclerosis (MS). Dendritic cells (DCs) induce immunity and tolerance and therefore represent a promising target for new immune-therapies of MS. Pathways of T cell tolerance that include deletion, anergy, and immune-suppression of autoreactive T cells were shown to confer protection from disease in autoimmune Experimental Acute Encephalomyelitis (EAE), a mouse model of MS. However, the specific mechanisms of tolerance mediated by DCs remain unclear. We recently discovered that Homeodomain Only Protein (Hopx) directs Treg cell-mediated immune unresponsiveness induced by DCs. Hopx is a transcription co-factor that differently regulates expression of c- jun/c-fos and other genes through its interactions with other proteins including Serum Response Factor (SRF). Our most recent findings reveal that DCs mediate tolerance through intimately linked pathways involving the early induction of tolerance in T cells that become unresponsive to activation in EAE, induce expression of Hopx and Hopx+/Foxp3neg cells can convert into Hopx+/Foxp3+ peripheral (p)Treg cells. These extrathymically- induced pTreg cells then mediate long-lasting tolerance to block autoimmune EAE. Hopx expressed in pTreg cells maintains the functions of these regulatory cells by inhibiting their expression of IL-2. Our results firmly establish Hopx as the first characterized transcription co-factor specifically required for DC- induced tolerance to avert autoimmunity, and they open a new area of investigation in immune tolerance mediated by DCs. Our long-term goals are to establish a novel and comprehensive model of Hopx functions in tolerance. We will reveal molecular pathways of Hopx in pTreg cells by clarifying functions of specific Hopx molecular targets including IL-2 in Aim 1. We will discern regulation of Hopx expression in tolerance in Aim 2. We will define the role for Hopx in diverse mechanisms of tolerance mediated by various types of DCs in Aim 3. The results of the proposed experiments may become a foundation of more selective and efficient therapies for MS as well as other types of autoimmune diseases.

描述（由申请人提供）：免疫耐受的破坏和促炎淋巴细胞的产生导致自身免疫性疾病，包括多发性硬化症（MS）。树突状细胞（DC）诱导免疫和耐受，因此代表了MS的新的免疫疗法的有前途的目标。T细胞耐受的途径，包括删除，无能，和自身反应性T细胞的免疫抑制被证明是赋予保护免受疾病的自身免疫性实验性急性脑脊髓炎（EAE），MS的小鼠模型。然而，由DC介导的耐受的具体机制仍不清楚。我们最近发现，同源结构域蛋白（Homeodomain Only Protein，Hopx）指导DC诱导的Treg细胞介导的免疫无反应性。Hopx是一种转录辅因子，其通过与包括血清应答因子（SRF）在内的其他蛋白质的相互作用来不同地调节c-jun/c-fos和其他基因的表达。我们最近的研究结果表明，DC通过密切相关的途径介导耐受性，这些途径涉及在EAE中对活化无反应的T细胞中早期诱导耐受性，诱导Hopx的表达，并且Hopx+/Foxp 3+细胞可以转化为Hopx+/Foxp 3+外周（p）Treg细胞。然后，这些胸腺外诱导的pTreg细胞介导持久的耐受性以阻断自身免疫性EAE。在pTreg细胞中表达的Hopx通过抑制它们的IL-2表达来维持这些调节细胞的功能。我们 这些结果坚定地确立了Hopx作为DC诱导的耐受性以避免自身免疫特异性所需的第一个特征性转录辅因子，并且它们开辟了DC介导的免疫耐受性的新研究领域。我们的长期目标是建立一个新的和全面的模型的Hopx功能的宽容。我们将通过阐明Aim 1中包括IL-2在内的特异性Hopx分子靶点的功能，揭示Hopx在pTreg细胞中的分子通路。我们将在目标2中辨别耐受中Hopx表达的调节。我们将定义Hopx在目标3中由各种类型的DC介导的多种耐受机制中的作用。所提出的实验的结果可能成为MS以及其他类型的自身免疫性疾病的更具选择性和有效性的治疗方法的基础。