Targeting OCA-B in multiple sclerosis

靶向多发性硬化症中的 OCA-B

• 批准号: 10446496
• 负责人: DEAN TANTIN
• 金额: $ 37.39万
• 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/10446496
• 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; 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; 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; 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.

项目总结 开发新的治疗方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发病的中心驱动力。我们的工作表明， 转录共调节因子OCA-B(基因符号Pou2af1)在刺激的原代CD4+T细胞中被诱导， 其中，它与其同源转录因子Oct1对接，以调节免疫调节靶基因，包括 IL2、IL17A、IFNG和CSF2(Gmcsf)。有趣的是，OCA-B只驱动这些基因的表达增加 在非常狭窄的条件下。OCA-B缺陷T细胞的初次刺激导致基因很少 表达的变化，然而，在培养休息后重新刺激这些细胞会导致基因表达 500倍或以上的变化。这些结果表明，OCA-B在特定条件下控制基因的表达 抗原再次相遇的条件。我们确定了分子机制，这涉及到去除 抑制染色质修饰，否则会累积以稳定沉默基因表达。重复 暴露抗原是自身免疫的一个必要特征。在体内，OCA-B的缺失导致T细胞发育 主要病原体的反应完好无损，但损害了CD4+T细胞记忆的建立。在两只小鼠中 而人类，具有记忆样表型的T细胞可以支持自身免疫，包括人类Gwas女士 研究发现OCAB/Pou2af1基因座以及OCA-B和Oct1结合部位的多态，AS MS驱动程序。这些发现提示了一个潜在的“治疗窗口”，在这个窗口中，靶向这一途径可以 用于治疗多发性硬化症，同时保护T细胞发育和主要免疫反应。始终如一地，我们有 研究表明，T细胞特异性的Oct1缺失阻断了实验性大鼠的临床和分子表现 自身免疫性脑脊髓炎(EAE)，同时保持对嗜神经病毒的免疫反应完好无损。亚奥理事会-B 淋巴限制表达模式，以及OCA-B生殖系缺失小鼠的存活率和生育力，使其成为一种 与10月1日相比，更有希望成为潜在的药物靶点。我们的初步数据表明，T细胞特异性OCA- B基因缺失还可以保护小鼠免受经典EAE的侵袭，并保护自身免疫倾向的非肥胖型糖尿病(NOD) 来自复发的EAE模型的小鼠，特别是在复发阶段。我们的主要假设是OCA-B 调节自身反应性、促炎症的Th1/Th17 CD4+T细胞中的关键基因，以推动MS的发病。我们 将通过两个具体目标实现研究目标，重点是亚奥理事会-B的必要性和充分性： 目的1：确定OCA-B促进EAE发病的细胞和分子基础。 目的2：验证OCA-B在EAE发病机制中的充分性。