In vivo modeling of autoantibody-induced optic neuritis

自身抗体诱导的视神经炎的体内模型

• 批准号: 10429925
• 负责人: Jeffrey L Bennett
• 金额: $ 17.16万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429925
• 关键词: Acute; Adrenal Cortex Hormones; Affect; Anatomy; Animal Experimentation; Animal Model; Animals; Anti-Inflammatory Agents; Antibodies; Astrocytes; Autoantibodies; Autoimmune; Automobile Driving; Axon; Blindness; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Characteristics; Clinical; Complement; Complement-Dependent Cytotoxicity; Cytolysis; Demyelinating Diseases; Demyelinations; Deposition; Development; Disease; Disease model; Disease remission; Electrophysiology (science); Electroretinography; Encephalomyelitis; Epitopes; Evaluation; Frequencies; Future; Goals; Histologic; Histopathology; Human; Immune; Immunoglobulin G; Immunologics; Infiltration; Inflammation; Inflammatory; Injury; Investigation; Measurement; Measures; Mediating; Methods; Modeling; Monitor; Multiple Sclerosis; Myelin; Nerve Tissue; Neuraxis; Neuromyelitis Optica; Neurons; Oligodendroglia; Operative Surgical Procedures; Ophthalmology; Optic Nerve; Optic Nerve Injuries; Optic Neuritis; Optical Coherence Tomography; Outcome; Pathology; Patients; Pattern; Phase; Plasmablast; Production; Prognosis; Rattus; Recombinant Antibody; Recovery; Recurrence; Resolution; Resources; Retina; Retinal Ganglion Cells; Risk; Sclerosis; Serum; Severities; Specificity; Spinal Cord; Structure; Subarachnoid Space; Techniques; Testing; Therapeutic Studies; Time; TimeLine; Tissues; Translational Research; Validation; Vision research; Visual; Visual Acuity; Visual evoked cortical potential; Visual system structure; aquaporin 4; axon injury; central nervous system demyelinating disorder; functional disability; glial activation; immunopathology; improved; in vivo; in vivo Model; injury and repair; injury recovery; innovation; multiple sclerosis patient; novel; oligodendrocyte-myelin glycoprotein; pathogenic autoantibodies; prevent; remyelination; response; tissue injury; tissue repair; tool; translational study; translational therapeutics; treatment response; visual dysfunction; water channel

Project Summary Vision loss from optic neuritis (ON) is a frequent consequence of autoimmune-mediated central nervous system (CNS) disorders such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein associated disease (MOGAD). The severity of vision loss, prognosis for recovery, response to therapy, and risk of recurrence varies significantly between disorders; however, our understanding of the pathophysiologic mechanisms driving these differences remain unclear. Reliable animal models that faithfully reproduce human MS-, NMOSD-, and MOGAD-specific pathology of the visual system are desperately needed to advance our understanding of disease pathobiology and advance treatment. MS, NMOSD, and MOGAD are differentiated by the production of disease-specific pathogenic autoantibodies. We hypothesize that these disease-specific autoantibodies initiate distinctive patterns of inflammatory optic nerve injury that clinically distinguish ON in MS, MNOSD and MOGAD. We intend to develop novel models of MS, NMOSD, and MOGAD ON by delivering disease-specific monoclonal recombinant antibodies (rAbs) or serum IgG into the rat retrobulbar space using a novel surgical technique. Our long-term goal is to generate transformative in vivo models of disease-specific antibody-mediated optic neuritis to advance translational research. In specific aim 1, we will measure the time course of functional impairment and inflammatory injury during the acute phase of autoantibody-driven optic neuritis. We will measure the anatomic and functional consequences of autoantibody-mediated optic neuritis in vivo using an array of tools that assess visual acuity, retinal structure, and electrophysiology. We will correlate our in vivo results to immunohistopathologic evaluations of complement deposition, myelin loss, and inflammatory cell infiltration in optic nerve tissue. In specific aim 2, we will quantify visual recovery and remyelination following autoantibody-driven optic neuritis. We will compare visual recovery and tissue repair in untreated and corticosteroid-treated animals using functional and structural measurements. These studies will further validate disease-specificity by comparing recovery in our animal ON models to those observed in their human counterparts. In vivo metrics will be correlated with measures of tissue pathology, remyelination, and axonal injury. The development and validation of these novel disease-specific models of ON will significantly advance our understanding of MS, NMOSD, and MOGAD ON pathobiology and provide an invaluable resource for future translational and therapeutic studies.

项目摘要 视力神经炎（ON）的视力丧失是自身免疫介导的中枢神经的经常结果 系统（CNS）疾病，例如多发性硬化症（MS），神经瘤谱谱系（NMOSD）和 髓磷脂少突胶质细胞糖蛋白相关疾病（Mogad）。视力丧失的严重性，预后 疾病之间的恢复，对治疗的反应和复发风险差异很大；但是，我们的 了解驱动这些差异的病理生理机制尚不清楚。可靠的动物 忠实地重现人类MS-，NMOSD-和MOGAD特异性病理的模型是 迫切需要促进我们对病理生物学和提前治疗的理解。 MS，NMOSD和MOGAD通过疾病特异性致病性而区分 自动抗体。我们假设这些特异性自身抗体启动了独特的模式 MS，MNOSD和MOGAD在临床上区分的炎症视神经损伤。我们打算发展 通过传递疾病特异性的单克隆重组，MS，NMOSD和Mogad的新型模型 使用一种新型的手术技术，抗体（RAB）或血清IgG进入大鼠后侧面空间。我们的长期 目标是生成疾病特异性抗体介导的视神经炎的体内模型的变革性转化模型 翻译研究。 在特定目标1中，我们将测量功能障碍和炎症性损伤的时间过程 自身驱动的视神经炎的急性期。我们将测量解剖和功能 自身抗体介导的视神经炎在体内的后果，使用一系列评估视力的工具， 视网膜结构和电生理学。我们将使我们的体内结果与免疫组织病理学相关联 对视神经组织中补体沉积，髓磷脂损失和炎症细胞浸润的评估。 在特定的目标2中，我们将在自动驱动的光学上量化视觉恢复和透明度 神经炎。我们将比较未经处理和皮质类固醇治疗的动物的视觉恢复和组织修复 功能和结构测量。这些研究将通过比较来进一步验证疾病特异性 我们动物在模型中恢复到人类对应物中观察到的模型。体内指标将是 与组织病理学，再生和轴突损伤的测量相关。 这些新型疾病特异性模型的开发和验证将显着推动我们的 了解病理生物学的MS，NMOSD和MOGAD，并为未来提供宝贵的资源 翻译和治疗研究。

项目成果

Quantitative Assessment of Subjective Symptoms and Corneal Sensitivity in Chronic Orbital Pain Patients.

慢性眼眶疼痛患者主观症状和角膜敏感性的定量评估。

• DOI: 10.1097/iop.0000000000002515
• 发表时间: 2024
• 期刊: Ophthalmic plastic and reconstructive surgery
• 影响因子: 2
• 作者: Lee,Grace;Kardon,RandyH;Nellis,JulieK;Pham,ChauM;Sales,ChristopherS;Carter,KeithD;Shriver,ErinM
• 通讯作者: Shriver,ErinM