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

基本信息

批准号：
9216116
负责人：
Robert C Axtell
金额：
$ 43.63万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9216116
关键词：
Address Affect Alpha Cell Animal Experiments Animal Model Antibodies Antigens Autoimmune Diseases Autoimmune Process Autoimmunity Autologous B-Lymphocyte Subsets B-Lymphocytes Biological CD3 Antigens CD4 Positive T Lymphocytes 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 Infiltration 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 TNFRSF5 gene 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

项目摘要

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.

概括：神经霉素炎Optica（NMO）是中枢神经系统的一种罕见但毁灭性的炎症性疾病（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批准的疗法对于NMO。实际上，许多MS疗法，最著名的是干扰素β（IFN-β），都会使NMO恶化。有限的疗法因为NMO证明这种疾病在神经病学方面有明确的需求。这个项目的目标是了解有助于NMO疾病活动的免疫病道。该提议的目的将解决三个连接但不同的问题，这些问题将影响NMO患者。 AIM 1将如何确定 IFN-β信号如何影响NMO患者的B细胞。这将通过细胞和转录组来实现分析患者的B细胞。 AIM 2将评估B细胞子集和T辅助器之间的直接相互作用 NMO和健康志愿者的细胞通过利用细胞培养技术。 AIM 3将利用实验性自身免疫性脑脊髓炎模型，以了解B细胞细胞因子如何效应Th17- 诱导神经免疫性疾病。该提案的前两个目标将是一项高度翻译的合作在DR之间。 Axtell，Lessard（自身免疫性遗传学家）和Pardo（OMRF的MS中心主任卓越）和加速的治疗项目（ACP）。临床专业知识和大量患者人群 OMRF MS Center和ACP将为该项目提供的目标将使这些目标得以实现。第三 AIM利用我们的力量在神经自动免疫的动物模型中，这将洞悉生物学 NMO背后的机制。关于人类受试者和机械动物的研究的结合该提案中概述的实验有可能深入了解病理过程基础和NMO。