In vivo modeling of autoantibody-induced optic neuritis

项目摘要 视神经炎（ON）导致的视力丧失是自身免疫介导的中枢神经系统疾病的常见后果， 中枢神经系统（CNS）疾病，如多发性硬化症（MS）、视神经肌萎缩症谱系障碍（NMOSD），和 髓鞘少突胶质细胞糖蛋白相关疾病（MOGAD）。视力丧失的严重程度， 恢复、治疗反应和复发风险在不同疾病之间有显著差异;然而， 对驱动这些差异的病理生理机制的理解仍不清楚。可靠的动物 忠实地再现人类视觉系统的MS、NMOSD和MOGAD特异性病理的模型是 迫切需要推进我们对疾病病理学的理解和先进的治疗。 MS、NMOSD和MOGAD通过产生疾病特异性病原体来区分。 自身抗体我们假设这些疾病特异性自身抗体启动了不同的免疫反应模式。 炎症性视神经损伤在MS、MNOSD和MOGAD中临床区分ON。我们准备开发 通过递送疾病特异性单克隆重组体的MS、NMOSD和MOGAD ON的新模型 抗体（rAbs）或血清IgG进入大鼠球后间隙使用一种新的手术技术。我们的长期 目的是产生疾病特异性抗体介导的视神经炎的转化性体内模型， 翻译研究 在具体的目标1中，我们将测量功能障碍和炎性损伤的时间过程， 自身抗体驱动的视神经炎的急性期我们将测量 使用一系列评估视敏度的工具， 视网膜结构和电生理学。我们将把我们的体内结果与免疫组织病理学联系起来， 评价视神经组织中的补体沉积、髓磷脂损失和炎性细胞浸润。 在具体的目标2中，我们将量化自身抗体驱动的光学损伤后的视力恢复和髓鞘再生。 神经炎。我们将比较未治疗和皮质类固醇治疗动物的视力恢复和组织修复， 功能和结构测量。这些研究将进一步验证疾病特异性， 在我们的动物ON模型中观察到的恢复与在它们的人类对应物中观察到的恢复相同。体内指标将是 与组织病理学、髓鞘再生和轴突损伤的测量相关。 这些新的ON疾病特异性模型的开发和验证将显著推进我们的研究。 了解MS，NMOSD和MOGAD对病理生物学的了解，并为未来提供宝贵的资源 转化和治疗研究。

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.