Comprehensive multimodal analysis of patients with neuroimmunological diseases

神经免疫疾病患者的综合多模态分析

基本信息

批准号：
7969693
负责人：
Bibiana Bielekova
金额：
$ 65.27万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7969693
关键词：
3-Dimensional Acute Antibodies Antigens Autologous B lymphocyte immortalization Biological Markers Biopsy Blinded Bypass CD8B1 gene CNS autoimmunity Central Nervous System Diseases Cerebrospinal Fluid Cervical spinal cord structure Clinical Code Collecting Cell Collection Complex Data Development Diagnosis Diagnostic Disease Encephalomyelitis Evaluation Failure Fibroblasts Functional disorder Goals Human Image Immune Immune Sera Immune response Immune system Inflammatory Knowledge Lead Literature Measures Mediating Medicine Methodology Molecular Multiple Sclerosis Myelin Natural History Nerve Degeneration Neuraxis Neurons Neuropsychiatric Systemic Lupus Erythematosus Organ Oxidative Stress Patients Phenotype Physiological Preparation Process Protocols documentation Rare Diseases Recovery Reporting Sampling Screening procedure Shapes Skin Source Staging T-Lymphocyte Tissues Transplantation Transverse Myelitis Uncertainty Work animal data central nervous system injury cohort disability effective therapy immunoregulation induced pluripotent stem cell nerve stem cell neuroimaging neuroprotection novel pathogen peripheral blood relating to nervous system repaired response

项目摘要

Neuroimmunological diseases of the central nervous system (CNS) represent a broad spectrum of very diverse diagnoses, most of which are considered rare disorders. With the exception of multiple sclerosis (MS), acute demyelinating encephalomyelitis (ADEM), transverse myelitis (TM) and CNS lupus, reported cohorts in the literature rarely exceed 10-20 patients, and it takes years to collect these numbers. Additionally, with the exception of MS, virtually all reports focus on clinical findings and there is a great paucity of data characterizing intrathecal or systemic immune responses in these patients. As a result, the pathophysiology of these diseases is poorly understood and effective therapies are very rare. Emerging data indicate that the immune response is shaped not only by pathogens, but also by the tissue where the inflammatory process develops. From this standpoint, CNS tissue is rather unique. Elegant animal data indicate that foreign grafts survive indefinitely if transplanted into CNS tissue, bypassing systemic presentation of its antigens, whereas they are readily rejected when transplanted into other organs. Indeed, interactions of T cells with neurons can shape T cell effector phenotype, from pathogenic to more regulatory. There is little doubt that these complex immunoregulatory mechanisms emerged as an assurance that CNS tissue, which is vital for the function and survival of the host, will be protected from inadvertent damage by the immune system. Therefore, the apparent failure of the immune system that presents clinically as CNS autoimmunity may originate as a breakdown of natural immunoregulatory mechanisms that govern CNS-immune system interactions. This project studies intrathecal and systemic immune responses in patients referred to NIB for diagnostic work-ups of neuroimmunological CNS disorders. The goal of this study is to define the pathophysiological mechanisms underlying the development of disability in immune-mediated disorders of the CNS and to distinguish these from physiological (and often beneficial) responses of the human immune system to CNS injury. We have established natural history protocol (09-N-0032) under which all untreated patients with suspected immune-mediated disorders of the CNS undergo detailed evaluation at NIB, consisting of the collection of clinical and paraclinical quantitative measures of disease activity and disability, standard and novel quantitative neuroimaging markers and immunological and molecular biomarkers originating from cerebrospinal fluid (CSF), serum and immune cells collected both from peripheral blood and CSF. Additionally, patients may undergo skin biopsy for collection of fibroblasts for their transformation into induced pluripotent stem (iPS) cells in order to develop autologous source of neural cells to study physiological neural-immune interactions in humans, which has not been possible thus far. All patients are coded and analysis of paraclinical, neuroimaging and molecular biomarkers are performed in an unbiased (i.e. blinded) fashion in order to define which biomarkers are associated with specific neuroimmunological disease or phenotype. Our results obtained so far are summarized below: 1. We have developed the methodology for expansion of CD4+ and CD8+ T cells from the limited sample of cerebrospinal fluid (CSF) 2. We have developed methodology for expansion and immortalization of B cells from the limited sample of CSF 3. We have developed methodology for 3 dimensional volumetric analysis of cervical spinal cord and are in the process of developing and validating other neuroimaging biomarkers of CNS tissue destruction (collaborative project) 4. The analysis of CSF antibody (Ab) reactivity to human myelin and different CNS antigens is in progress 5. We are developing and validating multiple biomarkers of intrathecal oxidative stress (collaborative project) 6. We are developing patient-derived iPS cells and, in preparation for differentiation of iPS cells to neural precursors, we are phenotypically characterizing human neural progenitors in their different stages of differentiation (collaborative project) The long-term objective of the study is to acquire knowledge that would allow us to therapeutically inhibit the pathogenic mechanisms and enhance repair mechanisms in immune-mediated CNS diseases, thereby minimizing the extent of CNS tissue damage and promoting recovery. Additionally, we expect that these studies will lead to the development of biomarkers (imaging, immunological and molecular) reflecting concurrent immune-mediated and neurodegenerative pathophysiological mechanisms and those that would able to distinguish among different diagnostic entities. This will lead to rational development and faster screening of process-specific therapies, and will permit the identification of patients with prevailing disease mechanisms, which is a requirement for an individualized approach to medicine. Ultimately, understanding the mechanisms of disease processes will impact the management of immune-mediated diseases of the CNS as a whole.

中枢神经系统（CNS）的神经免疫性疾病代表了非常多样化的诊断的广泛范围，其中大多数被认为是少数疾病。除多发性硬化症（MS）外，急性脱髓鞘脑脊髓炎（ADEM），横向骨髓炎（TM）和CNS狼疮报告在文献中报道了同类文献很少超过10-20名患者，并且需要数年的时间才能收集这些数字。此外，除了MS外，几乎所有报告都集中在临床发现上，并且这些患者中表征鞘内或全身免疫反应的数据很少。结果，这些疾病的病理生理学知之甚少，有效疗法非常罕见。新兴数据表明，免疫反应不仅由病原体形成，而且由炎症过程发展的组织形成。从这个角度来看，CNS组织是相当独特的。优雅的动物数据表明，如果移植到中枢神经系统组织中，外国移植物将无限期地生存，绕过了其抗原的全身性表现，而将它们移植到其他器官中时很容易被拒绝。实际上，T细胞与神经元的相互作用可以塑造从致病性到更调节性的T细胞效应表型。毫无疑问，这些复杂的免疫调节机制出现是一种保证，即CNS组织对宿主的功能和存活至关重要，将受到免疫系统的无意损害。因此，由于CNS自身免疫性，在临床上呈现的免疫系统的明显失败可能起源于控制CNS-免疫系统相互作用的天然免疫调节机制。该项目研究了转介给NIB的患者的鞘内和全身免疫反应，用于神经免疫性中枢神经系统疾病的诊断检查。这项研究的目的是确定中枢神经系统免疫介导的疾病中残疾发展的基础的病理生理机制，并将其与人类免疫系统对CNS损伤的生理（且经常有益）反应区分开。我们已经建立了自然历史方案（09-N-0032），在该方案下，所有未经治疗的中枢神经系统的未经治疗的患者在NIB处进行了详细的评估，包括收集临床和旁层次的疾病活性和残疾的疾病活性，标准和新颖的神经性神经疾病和免疫学的熟人（CERENALICAL ECORALICAL ECORPROCTALICALICAL INFIRALICAL ECORTIAL ECORPORTAILIAL ECORPROCTARICAL EREF）的CN，该测量值包括从外周血和CSF收集的免疫细胞和免疫细胞。此外，患者可能会进行皮肤活检以收集成纤维细胞的转化为诱导多能干（IPS）细胞，以开发神经细胞的自体源以研究人类的生理神经免疫相互作用，到目前为止尚未实现。所有患者均进行编码，并以无偏见的（即盲人）方式进行层链，神经影像学和分子生物标志物，以定义哪些生物标志物与特定的神经免疫学疾病或表型相关。到目前为止，我们获得的结果总结了下面： 1。我们开发了从有限的脑脊液样品（CSF）样品中扩展CD4+和CD8+ T细胞的方法。 2。我们开发了从有限的CSF样品中B细胞扩展和永生化的方法论 3。我们为颈脊髓的3维体积分析开发了方法，并正在开发和验证中枢神经系统组织破坏的其他神经成像生物标志物（协作项目） 4。对人髓磷脂和不同CNS抗原的CSF抗体（AB）反应性的分析正在进行中 5。我们正在开发和验证鞘内氧化应激的多种生物标志物（协作项目） 6。我们正在开发患者衍生的IPS细胞，并准备将IPS细胞与神经前体分化，我们在表型上表征了人类神经祖细胞在不同的分化阶段（协作项目）该研究的长期目标是获取知识，使我们能够治疗抑制病原机制并增强免疫介导的中枢神经系统疾病中的修复机制，从而最大程度地减少中枢神经系统组织损害的程度并促进康复。此外，我们预计这些研究将导致生物标志物（成像，免疫学和分子）的发展，反映出并发的免疫介导的和神经退行性的病理生理机制以及能够区分不同诊断实体的生物标志物。这将导致合理发展和更快的过程特定疗法筛查，并允许鉴定具有流行疾病机制的患者，这是对医学方法的要求。最终，了解疾病过程的机制将影响整个中枢神经系统的免疫介导的疾病的管理。