In vivo modeling of autoantibody-induced optic neuritis

项目摘要 视神经炎引起的视力丧失是自身免疫介导的中枢神经的常见后果 系统(CNS)疾病，如多发性硬化症(MS)、视神经脊髓炎谱性疾病(NMOSD)，以及 髓鞘少突胶质细胞糖蛋白相关性疾病(MOGAD)。视力丧失的严重程度，预后 康复、对治疗的反应和复发风险在不同的疾病之间差异很大；然而，我们的 对导致这些差异的病理生理机制的了解仍不清楚。可靠的动物 忠实地复制人类MS、NMOSD和MOGAD特定视觉系统病理的模型是 迫切需要提高我们对疾病病理生物学的理解，推进治疗。 MS、NMOSD和MOGAD是通过产生特定于疾病的致病物质来区分的 自身抗体。我们推测，这些疾病特异性自身抗体启动了不同的模式 炎性视神经损伤在MS、MNOSD和MOGAD中的临床鉴别。我们打算发展 通过提供疾病特异性单抗重组的MS、NMOSD和MOGAD的新模型 利用一种新的外科技术，将抗体(RAB)或血清免疫球蛋白(Ig G)导入大鼠球后间隙。我们的长期合作 目标是建立疾病特异性抗体介导性视神经炎的体内转化模型，以推动 翻译研究。 在特定目标1，我们将测量功能损害和炎性损伤的时间进程 自身抗体驱动的视神经炎的急性期。我们将测量解剖和功能 使用一系列评估视力的工具在体内评估自身抗体介导的视神经炎的后果， 视网膜结构和电生理学。我们将把我们体内的结果与免疫组织病理学联系起来 视神经组织中补体沉积、髓鞘丢失和炎性细胞浸润的评估。 在特定的目标2中，我们将量化自身抗体驱动的视神经损伤后的视力恢复和重新髓鞘形成。 神经炎。我们将比较未经治疗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 在我们的动物模型上观察到的恢复情况与在人类同行中观察到的结果相比。体内指标将是 与组织病理学、髓鞘再生和轴突损伤相关。 这些新的疾病特异性ON模型的开发和验证将大大促进我们的 了解MS、NMOSD和MOGAD的病理生物学知识，为未来提供宝贵的资源 翻译和治疗研究。

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.