Pathogenic B cell and T helper cell interactions in Neuromyelitis Optica

视神经脊髓炎中致病性 B 细胞和 T 辅助细胞的相互作用

• 批准号: 10178030
• 负责人: Robert C Axtell
• 金额: $ 42.32万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178030
• 关键词: Address; Affect; Animal Experiments; Animal Model; Anti-CD40; Antibodies; Antigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Autologous; B-Lymphocyte Subsets; B-Lymphocytes; Biological; CD3 Antigens; Cell Communication; Cell Culture Techniques; Cell physiology; Cells; Central Nervous System Diseases; Chimeric Proteins; Clinical; Clinical Trials; Coculture Techniques; Collaborations; Coupled; Data; Development; Disease; Dose; Enzyme-Linked Immunosorbent Assay; Experimental Autoimmune Encephalomyelitis; Experimental Designs; FDA approved; Flare; Flow Cytometry; Genes; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; IL8RB gene; Immune; Impairment; Individual; Inflammation; Inflammatory; Interferon-beta; Interferons; Knockout Mice; Lesion; Memory B-Lymphocyte; Modeling; Molecular; Molecular Medicine; Monoclonal Antibodies; Multiple Sclerosis; Mus; NF-kappa B; Neuraxis; Neurology; Neuromyelitis Optica; Neutrophil Infiltration; Optic Nerve; Optic Neuritis; Pathogenesis; Pathogenicity; Pathologic; Pathologic Processes; Pathway interactions; Patients; Play; Production; Property; Publishing; RNA; Reactive Oxygen Species; Relapse; Research; Rodent; Role; Serine; Signal Transduction; Spinal; Spinal Cord; Supporting Cell; System; Systemic Lupus Erythematosus; T cell differentiation; T memory cell; T-Lymphocyte; Techniques; Testing; Tetanus Toxin; Th1 Cells; Therapeutic; Tissues; Translations; Variant; Whole Blood; anti-IgM; aquaporin 4; belimumab; cell type; chemokine; cytokine; healthy volunteer; human subject; in vivo Model; insight; multiple sclerosis patient; nervous system disorder; neutrophil; new therapeutic target; novel; novel therapeutics; patient population; reconstitution; response; rituximab; therapeutic target; trafficking; transcriptomics

Summary: Neuromyelitis optica (NMO) is a rare but devastating inflammatory disorder of the central nervous system (CNS) that primarily affects the optic nerves and spinal cord. NMO was initially characterized as a subset of multiple sclerosis (MS), but is now considered a distinct disease. Currently, there are no FDA approved therapies for NMO. In fact, many MS therapies, most notably interferon-beta (IFN-β), worsens NMO. The limited therapies for NMO demonstrates that this disease has clear unmet needs in neurology. The goal of this project is to understand the immune pathways that contribute to disease activity in NMO. The aims of this proposal will address three connected but distinct issues that will have an impact NMO patients. Aim 1 will how determine how IFN-β signaling effects B-cells from patients with NMO. This will be achieved by CyTOF and transcriptomic analysis of B-cells from patients. Aim 2 will assess the direct interaction between B-cell subsets and T helper cells from NMO and healthy volunteers by utilizing cell culturing techniques. Aim 3 will utilize variations of experimental autoimmune encephalomyelitis model to understand how the B-cells cytokines effect TH17- induced neuro-autoimmune disease. The first two aims of this proposal will be a highly translation collaboration between Drs. Axtell, Lessard (autoimmune geneticist) and Pardo (the director of OMRF's MS Center of Excellence), and the Accelerated Cure Project (ACP). The clinical expertise and large patient population of the OMRF MS Center and the ACP will provide to this project will enable these aims to be accomplished. The third aim utilizes our strength in animal models of neuro-autoimmunity that will give insight into the biological mechanisms behind NMO. The combination of research on human subject and the mechanistic animal experiments outlined in this proposal have the potential to give deep insight into pathological processes that underlie and NMO.

总结： 视神经肌萎缩症（NMO）是一种罕见但破坏性的中枢神经系统炎症性疾病 (CNS)主要影响视神经和脊髓NMO最初被描述为 多发性硬化症（MS），但现在被认为是一种独特的疾病。目前，没有FDA批准的治疗方法 对于NMO。事实上，许多MS疗法，最显著的是干扰素-β（IFN-β），抑制NMO。有限的治疗 表明这种疾病在神经病学方面有明显的未满足的需求。该项目的目标是 了解导致NMO疾病活动的免疫途径。本提案的目的是 解决三个相互关联但又截然不同的问题，这些问题将对NMO患者产生影响。目标1将如何确定 IFN-β信号传导如何影响NMO患者的B细胞。这将通过CyTOF和转录组学来实现 分析患者的B细胞。目的2将评估B细胞亚群和辅助性T细胞之间的直接相互作用 利用细胞培养技术从NMO和健康志愿者中获得细胞。目标3将利用 实验性自身免疫性脑脊髓炎模型，以了解B细胞细胞因子如何影响TH 17- 诱发的神经自身免疫性疾病该提案的前两个目标将是高度翻译合作 Axtell博士，Lessard（自身免疫遗传学家）和Pardo（OMRF MS中心主任， 加速治愈项目（ACP）。临床专业知识和庞大的患者人群， OMRF MS中心和ACP将为该项目提供支持，以实现这些目标。第三 aim利用我们在神经自身免疫动物模型中的优势， NMO背后的机制人体研究与机械动物研究的结合 该提案中概述的实验具有深入了解病理过程的潜力， underlie和NMO。

项目成果

Current and Future Biomarkers in Multiple Sclerosis.

• DOI: 10.3390/ijms23115877
• 发表时间: 2022-05-24
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Pertussis Toxin Inhibits Encephalitogenic T-Cell Infiltration and Promotes a B-Cell-Driven Disease during Th17-EAE.

• DOI: 10.3390/ijms22062924
• 发表时间: 2021-03-13
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Maria Z;Turner E;Agasing A;Kumar G;Axtell RC
• 通讯作者: Axtell RC

ELTD1 as a biomarker for multiple sclerosis: Pre-clinical molecular-targeted studies in a mouse experimental autoimmune encephalomyelitis model.

• DOI: 10.1016/j.msard.2021.102786
• 发表时间: 2021-04
• 期刊: Multiple sclerosis and related disorders
• 影响因子: 4
• 作者: Towner RA;Smith N;Zalles M;Morris S;Toliver M;Saunders D;Lerner M;Kumar G;Axtell RC
• 通讯作者: Axtell RC

Interferon-β Intensifies Interleukin-23-Driven Pathogenicity of T Helper Cells in Neuroinflammatory Disease.

• DOI: 10.3390/cells10082139
• 发表时间: 2021-08-20
• 期刊: Cells
• 影响因子: 6
• 作者: Agasing A;Quinn JL;Kumar G;Axtell RC
• 通讯作者: Axtell RC

Dual Role of B Cells in Multiple Sclerosis.

• DOI: 10.3390/ijms24032336
• 发表时间: 2023-01-25
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Kumar, Gaurav;Axtell, Robert C.
• 通讯作者: Axtell, Robert C.