Targeting OCA-B in multiple sclerosis

靶向多发性硬化症中的 OCA-B

• 批准号: 10563206
• 负责人: DEAN TANTIN
• 金额: $ 41.44万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-11 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563206
• 关键词: Alleles; Animals; Antigens; Autoimmune; Autoimmune Diabetes; Autoimmunity; B-Lymphocytes; Binding Sites; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cervical lymph node group; Chromatin; Clinical; Conditioned Reflex; Cytoprotection; Data; Development; Docking; Drug Targeting; Environment; Evaluation; Excision; Experimental Autoimmune Encephalomyelitis; Fertility; Flow Cytometry; Gene Expression; Gene Expression Profiling; Gene Silencing; Genes; Genetic Polymorphism; Genetic Transcription; Goals; Histones; Human; Immune; Immune response; Impairment; Inbred NOD Mice; Inflammatory; Islets of Langerhans; Knockout Mice; Lightning; Lymphoid; Memory; Modeling; Molecular; Multiple Sclerosis; Mus; Non obese; Organ; Pathogenesis; Pathway interactions; Pattern; Phase; Phenotype; Relapse; Reporter; Repression; Rest; T-Cell Development; T-Lymphocyte; TCF Transcription Factor; Technology; Testing; Therapeutic; Transcription Factor AP-1; Transplantation; Work; autoreactive T cell; autoreactivity; cell type; chromatin modification; diabetic; experimental study; genome wide association study; immune function; immunoregulation; in vivo; inhibitor; memory CD4 T lymphocyte; mouse model; multiple sclerosis treatment; neurotropic virus; nuclear factors of activated T-cells; pathogen; permissiveness; polarized cell; pre-clinical; preservation; public health relevance; recruit; response; single-cell RNA sequencing; transcription factor

PROJECT SUMMARY Developing new treatments to block multiple sclerosis (MS) while keeping beneficial immune function intact constitutes a major goal in the field. T cells are central drivers of MS pathogenesis. Our work shows that the transcriptional co-regulator OCA-B (gene symbol Pou2af1) is induced in stimulated primary CD4+ T cells, where it docks with its cognate transcription factor Oct1 to regulate immunomodulatory target genes including Il2, Il17a, Ifng, and Csf2 (Gmcsf). Interestingly, OCA-B drives the elevated expression of these genes only under a very narrow range of conditions. Primary stimulation of OCA-B deficient T cells results in few gene expression changes, however re-stimulating these cells after resting in culture results in gene expression changes of 500-fold or more. These results indicate that OCA-B controls gene expression specifically under conditions of antigen reencounter. We identified the molecular mechanism, which involves the removal of inhibitory chromatin modifications that otherwise accumulate to stably silence gene expression. Repeated antigen exposures are a necessary feature of autoimmunity. In vivo, OCA-B loss leaves T cell development and primary pathogen responses intact, but impairs the establishment of CD4+ T cell memory. In both mice and humans, T cells with memory-like phenotypes can underlie autoimmunity including MS. Human GWAS studies identify polymorphisms at the Ocab/Pou2af1 locus, as well as in binding sites for OCA-B and Oct1, as MS drivers. These findings suggest a potential “therapeutic window” in which targeting this pathway can be used to treat MS while preserving T cell development and primary immune responses. Consistently, we have shown that T cell-specific deletion of Oct1 blocks clinical and molecular manifestations of experimental autoimmune encephalomyelitis (EAE) while keeping immune responses to neurotropic viruses intact. OCA-B’s lymphoid-restricted expression pattern, and the viability and fertility of OCA-B germline null mice, make it a more promising potential drug target compared to Oct1. Our preliminary data indicate that T cell-specific OCA- B deletion also protects mice from classical EAE, and protects autoimmune-prone non-obese diabetic (NOD) mice from a relapsing EAE model, specifically at the relapse phase. Our overarching hypothesis is that OCA-B regulates key genes in autoreactive, pro-inflammatory Th1/Th17 CD4+ T cells to drive MS pathogenesis. We will realize the objectives of the study via two specific aims focused on OCA-B necessity and sufficiency: Aim 1: Determine the cellular and molecular basis of OCA-B promotion of EAE pathogenesis. Aim 2: Test OCA-B’s sufficiency in EAE pathogenesis.

项目概要 开发新疗法来阻止多发性硬化症 (MS)，同时保持有益的免疫功能完整 构成了该领域的一个主要目标。 T 细胞是 MS 发病机制的核心驱动因素。我们的工作表明 转录共调节因子 OCA-B（基因符号 Pou2af1）在受刺激的原代 CD4+ T 细胞中被诱导， 它与同源转录因子 Oct1 对接来调节免疫调节靶基因，包括 Il2、Il17a、Ifng 和 Csf2 (Gmcsf)。有趣的是，OCA-B 仅驱动这些基因的表达升高 在非常狭窄的条件范围内。 OCA-B 缺陷 T 细胞的初次刺激导致很少的基因 表达发生变化，但是在培养物中休息后重新刺激这些细胞会导致基因表达 变化500倍以上。这些结果表明 OCA-B 在特定条件下控制基因表达 抗原再次相遇的条件。我们确定了分子机制，其中涉及去除 抑制性染色质修饰会累积，从而稳定地沉默基因表达。重复 抗原暴露是自身免疫的一个必要特征。在体内，OCA-B 缺失会影响 T 细胞的发育 和原发病原体反应完好，但损害 CD4+ T 细胞记忆的建立。在两只小鼠中 对于人类和人类来说，具有记忆样表型的 T 细胞可能是包括多发性硬化症在内的自身免疫性疾病的基础。人类全基因组关联分析 研究确定了 Ocab/Pou2af1 基因座以及 OCA-B 和 Oct1 结合位点的多态性，如 女士司机。这些发现表明了一个潜在的“治疗窗口”，其中可以针对该途径 用于治疗多发性硬化症，同时保留 T 细胞发育和初级免疫反应。一贯地，我们有 结果表明，T 细胞特异性删除 Oct1 可阻断实验性临床和分子表现 自身免疫性脑脊髓炎（EAE），同时保持对神经病毒的免疫反应完整。 OCA-B 的 淋巴限制性表达模式以及 OCA-B 种系缺失小鼠的活力和生育力，使其成为 与Oct1相比更有希望的潜在药物靶点。我们的初步数据表明 T 细胞特异性 OCA- B 缺失还可以保护小鼠免受经典 EAE 的侵害，并保护易患自身免疫性非肥胖糖尿病 (NOD) 来自复发性 EAE 模型的小鼠，特别是在复发阶段。我们的总体假设是 OCA-B 调节自身反应性促炎性 Th1/Th17 CD4+ T 细胞中的关键基因，以驱动 MS 发病机制。我们 将通过关注 OCA-B 必要性和充分性的两个具体目标来实现研究目标： 目标 1：确定 OCA-B 促进 EAE 发病机制的细胞和分子基础。 目标 2：测试 OCA-B 在 EAE 发病机制中的充分性。