Pathogenic Mechanism of Intrathecally Synthesized Immunoglobulins in a Mouse Model of Progressive Multiple Sclerosis

鞘内合成免疫球蛋白在进行性多发性硬化症小鼠模型中的致病机制

基本信息

批准号：
10673659
负责人：
Michael R Linzey
金额：
$ 0.73万
依托单位：
DARTMOUTH-HITCHCOCK CLINIC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-22 至 2023-09-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10673659
关键词：
Affect Agreement Anaphylatoxins Antibodies Antigen-Antibody Complex Antigens Area Automobile Driving Axon Binding Biological Markers Cells Central Nervous System Central Nervous System Diseases Cerebrospinal Fluid Characteristics Chronic Chronic Phase of Disease Classical Complement Pathway Clinical Cognitive Complement Complement 1q Complement-Dependent Cytotoxicity Complex Demyelinating Diseases Demyelinations Deposition Development Disease Disease Outcome Disease Progression Engineering Evaluation Flow Cytometry Gene Expression Goals Histologic Histology Imaging Techniques Immune Immunofluorescence Immunologic Immunoglobulins Immunologics Inflammation Inflammation Mediators Inflammatory Intraventricular Lesion Light Lytic Magnetic Resonance Imaging Manuscripts Measurement Mentors Modeling Motor Multiple Sclerosis Mus Nerve Degeneration Nervous System Trauma Neurodegenerative Disorders Neurologic Symptoms Opsonin Outcome Pathogenicity Pathologic Pathology Phenotype Play Preparation Proteins Relapse Role Severity of illness TMEV Techniques Testing Therapeutic Tissues Work antibody and antigen binding antibody-dependent cell cytotoxicity axon injury blood-brain barrier crossing chemokine chronic inflammatory disease cognitive function complement pathway complement system cytokine cytotoxic cytotoxicity diagnostic criteria disability drug discovery follow-up glial activation gray matter improved in vivo insight molecular diagnostics mouse model multiple sclerosis patient nanobodies neurodegenerative phenotype neurofilament neuroinflammation neuron loss neuroprotection novel prevent recruit spatial relationship success white matter

项目摘要

Project Summary/Abstract Relapsing and progressive multiple sclerosis (MS) are characterized by an intrathecal synthesis of immunoglobulins (IIgS). This occurs throughout the disease and is the only widely agreed upon molecular diagnostic criteria for MS. A growing body of evidence also suggests that IIgS correlates with MS disease progression, although the pathological role of these antibodies remains to be determined. Cytotoxic activities in the central nervous system (CNS) are critical determinants of MS disease progression. Interestingly, antibodies can activate two distinct cytotoxic mechanisms: antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Therefore, I initially hypothesized that, in MS, IIgS triggers ADCC and CDC within the CNS, thereby accruing CNS damage and worsening disease progression. Thus, over the past few years, the primary goal of my work has been to define the cytotoxic activity of these Igs by using Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) as a model of progressive MS. Particularly, I have been focusing on CDC and the classical complement pathway. The first component of the classical complement pathway (C1q) recognizes and binds to Igs complexed to antigen and initiates the complement cascade, ultimately triggering CDC. Since the results of my studies suggest higher levels of C1q in the CNS indicate more severe clinical and pathological disease, I developed a refined working hypothesis. Thus, I now hypothesize that therapeutic inhibition of C1q in the CNS of TMEV-IDD mice will prevent disease progression by reducing neuroaxonal damage and neuroinflammation. I will test this hypothesis by accomplishing the following three aims: Aim 1 will demonstrate that anti-C1q treatment improves clinical outcomes. To accomplish this aim, TMEV- IDD mice will be treated with either an intraventricularly injected murine anti-C1q antibody (M1) or a systemically administered anti-C1q camelid VHH antibody (aka nanobody). Motor and cognitive outcomes will be evaluated. Aim 2 will demonstrate that anti-C1q treatment reduces neuroaxonal damage. To accomplish this aim, neuroaxonal damage in treated vs. untreated mice will be assessed throughout the disease by 1) measurement of cerebrospinal fluid (CSF) biomarkers of neuroaxonal damage, 2) histology, and 3) quantitative magnetic resonance imaging (MRI) techniques. Aim 3 will demonstrate that anti-C1q treatment reduces neuroinflammation. To accomplish this aim, neuroinflammation will be assessed in treated and untreated mice by 1) flow cytometry, 2) immunofluorescence, and 3) measurement of intrathecally produced inflammatory biomarkers. Overall, this work will provide compelling evidence for the significant role played by IIgs in PMS, thereby defining a new paradigm for its treatment.

项目摘要/摘要复发和进行性多发性硬化症（MS）的特征是鞘内合成免疫球体（IIG）。女士越来越多的证据的诊断标准也表明，IIG与MS疾病相关进展，Althooth综合症的病理作用尚待确定。中心神经系统（CNS）中的细胞毒性活性是MS疾病进展的关键决定因素。杂文，抗体可以激活两种不同的细胞毒性机制：抗体依赖性细胞介导细胞毒素（ADCC）和依赖性细胞毒性（CDC）。 MS，IIG触发中枢神经系统内的ADCC ADCC和CDC，从而造成CNS损害和恶化的疾病因此，在您的通过时，我的工作的主要目标是定义细胞毒性活动通过使用Theiler的鼠脑脊髓炎病毒诱导的脱髓鞘疾病（TMEV-IDD）作为一种Ig 尤其是进步女士的模型，我一直专注于CDC和经典补体途径。经典补体途径（C1Q）的第一个组成部分识别并结合了IGS 抗原和启动汇编级联，最终触发CDC。中枢神经系统中较高水平的C1Q表明更严重的临床和病理性疾病，我出现了一种精制工作假设。通过减少神经肌损伤和神经炎症来预防疾病的进展通过完成以下三个AM来假设： AIM 1将证明抗C1Q治疗可以改善临床结果。 IDD小鼠将通过注射鼠类C1Q抗体（M1）或系统地治疗施用的抗C1Q Camelid VHH抗体（又称纳米病）。 AIM 2将证明抗C1Q治疗可减少神经障碍损伤。在治疗的和未处理的小鼠中，神经司长损伤将通过1）测量来评估该疾病脑脊液（CSF）神经司长损伤的生物标志物，2）组织学和3）定量磁性共振成像（MRI）技术。 AIM 3将证明抗C1Q治疗可减少神经炎症。神经炎症将通过1）流式细胞测量法在处理和未经试验的小鼠中评估，2）免疫荧光， 3）测量鞘内产生的炎症生物标志物。总体而言，这项工作将为IIG在PMS中扮演的重要作用提供令人信服的证据定义新的IS治疗范式。