Optic nerve degeneration in experimental autoimmune encephalomyelitis

The mechanisms of axonal and neuronal degeneration causing disability in optic neuritis and multiple sclerosis are poorly understood. Here we describe the role of mitochondria, oxidative stress and the effects of modulating antioxidant gene expression in the optic nerves of mice induced with experimental autoimmune encephalomyelitis, with a focus on long-term neuroprotection. Oxidative injury to the mitochondrion began prior to inflammatory cell infiltration and continued. It affected subunits of the respiratory chain, glycolysis and a chaperone critical to the stabilization and import of proteins. Oxidative products were associated with loss of membrane potential, mitochondrial degeneration and severe axonal loss. Reductions in ATP synthesis were even greater than those associated with mitochondrial diseases. Increasing SOD2 levels by viral mediated gene transfer rescued ATP synthesis, suppressed myelin fiber injury and increased retinal ganglion cell survival 1 year later.     

Optic neuropathy induced by reductions in mitochondrial superoxide dismutase

PURPOSE: Reactive oxygen species (ROS) are suspected to play a pivotal role in the pathogenesis of Leber hereditary optic neuropathy (LHON), caused by mutated complex I subunit genes. It seems surprising that optic neuropathy has not been described in animals with a knockout of genes encoding critical anti-ROS defenses. If ROS have a role in the optic nerve injury of LHON, then increasing mitochondrial levels of ROS should induce optic neuropathy. METHODS: To develop an animal model system for study of oxidative injury to the optic nerve, mitochondrial defenses were decreased against ROS by designing hammerhead ribozymes to degrade SOD2 mRNA. Several potential ribozymes were analyzed in vitro. The one with the best kinetic characteristics was cloned into a recombinant adeno-associated virus (rAAV) vector for delivery and testing in cells and animals. The effects of the AAV-expressing ribozyme on murine cell growth, SOD2 mRNA and protein, cellular ROS levels, and apoptosis were evaluated by RNase protection assay, immunoblot analysis, and ROS- and apoptosis-activated fluorescent probes. The rAAV-ribozyme was then injected into the eyes of DBA/1J mice, and the effect on the optic nerve was evaluated by ocular histopathologic examination. RESULTS: The AAV-expressing ribozyme decreased SOD2 mRNA and protein levels by as much as 85%, increased cellular superoxide, reduced mitochondrial membrane potential, and culminated in the death of infected cell lines by apoptosis without significantly altering complex I and III activity, somewhat spared in the most common LHON mutation (G11778A), although adenosine triphosphate (ATP) synthesis is markedly reduced. When inoculated into the eyes of mice, the AAV-expressing ribozyme led to loss of axons and myelin in the optic nerve and ganglion cells in the retina, the hallmarks of optic nerves examined at autopsy of patients with LHON. CONCLUSIONS: The striking similarity of the optic neuropathy to the histopathology of LHON is powerful evidence supporting ROS as a key factor in the pathogenesis of LHON.     

Long-term suppression of neurodegeneration in chronic experimental optic neuritis: antioxidant gene therapy

PURPOSE: To test in mice with experimental autoimmune encephalomyelitis (EAE) a strategy designed to treat patients at risk for axonal degeneration and persistent visual loss from optic neuritis and multiple sclerosis. METHODS: The authors cloned the human extracellular superoxide dismutase (ECSOD) or catalase (CAT) gene into recombinant adenoassociated virus (AAV). Transgene expression was evaluated by immunochemistry of infected RGC-5 cells and after intravitreal injection of AAV-ECSOD or AAV-CAT, or both, into the right eyes of DBA/1J mice. Control cells and left eyes were inoculated with AAV-GFP. Animals were sensitized for EAE, followed by serial contrast-enhanced MRI for 6 months, and then were euthanatized. The effects of ECSOD and CAT modulation on the EAE optic nerve were gauged by computerized analysis of optic nerve volume, myelin fiber area, axonal cell loss, and retinal ganglion cell (RGC) loss. RESULTS: Western blot analysis of infected RGC-5 cells revealed that expression of ECSOD increased 15-fold and that of CAT increased 3.5-fold. One month after intraocular injections, transgene expression increased 4-fold for AAV-ECSOD and 3.3-fold for AAV-CAT. Six months after intraocular injections and EAE sensitization, combination therapy with ECSOD and catalase decreased RGC loss by 29%, optic nerve demyelination by 36%, axonal loss by 44%, and cellular infiltration by 34% compared with the contralateral control eyes inoculated with AAV-GFP. Compared with the normal optic nerve, it limited RGC loss to 9%. CONCLUSIONS: Viral-mediated delivery of antioxidant genes provides long-lasting suppression against neuronal and axonal loss associated with permanent visual disability in patients with optic neuritis and multiple sclerosis.     

活性氧清除剂对实验性视神经炎作用的研究进展

活性氧簇(ROS)是神经系统脱髓鞘及血脑屏障破坏的媒介.ROS包括过氧化物及笑气(NO),由浸润的炎症细胞释放,其代谢产物包括过氧化氢(H202)、过(氧化)亚硝酸盐及羟基.在实验性视神经炎的动物模型中,发生了神经系统的脱髓鞘及血脑屏障的破坏,这和炎症细胞释放的ROS增加有密切关系,因此活性氧清除剂在保护炎症中的视神经免受氧化应激损伤方面显得尤为重要.本文针对近年来活性氧清除剂对实验性视神经炎的治疗研究作一综述,从而也从病因上对视神经炎的治疗进行探讨.     

米诺环素对急性视神经炎视神经轴突及Caspase-3表达的影响

目的:探讨米诺环素对急性视神经炎的影响,并与甲基强的松龙比较。方法:雌性Wistar大鼠22只随机分为正常组、EAE组、米诺环素组、甲基强的松龙组(MP组)。观察视神经病理改变,免疫组织化学法检测视网膜神经节细胞(retinal ganglion cells,RGCs)中Caspase-3蛋白表达。结果:EAE组视神经光镜下表现为神经纤维空泡样变性,轴突不规则肿胀,大量炎性细胞浸润。EAE组、米诺环素组、MP组与正常组视神经轴突占横切面积比例相比,差异均有显著统计学意义(P<0.01),米诺环素组、MP组与EAE组间的差异均有统计学意义(P<0.05)。正常大鼠视网膜几乎未见Caspase-3蛋白表达,EAE组、MP组与米诺环素组间的差异均有统计学意义(P<0.05),MP组与EAE组间的差异有统计学意义(P<0.05)。结论:甲基强的松龙可减轻脱髓鞘性视神经炎轴突损伤,但不能减少RGCs中Caspase-3的表达。米诺环素可下调Caspase-3在视网膜中表达,提示米诺环素可通过抑制RGCs中Caspase-3活性,介导对脱髓鞘性视神经炎RGCs的保护作用。     

Anti-myelin basic protein antibody in experimental allergic optic neuritis and encephalomyelitis

We produced demyelinating optic neuritis and encephalomyelitis in juvenile strain 13 guinea pigs by sensitization with optic nerve myelin. Three distinct clinical courses were noted: a severe, acute optic neuritis associated with a rapidly fatal encephalomyelitis; a mild, chronic optic neuritis with a nonfatal encephalomyelitis; and an initially mild disease followed by an acute exacerbation of optic neuritis and fatal encephalomyelitis. Clinically mild disease was associated with elevated levels of anti-myelin basic protein antibody, while severe disease was associated with extremely low antibody levels.     

Acute optic neuritis associated with immunization with the CNS myelin proteolipid protein.

Optic nerve tissue for SJL/J mice immunized with the central nervous system (CNS) myelin-specific proteolipid protein (PLP) was examined for histopathologic evidence of optic neuritis. Optic nerves isolated 17 d after immunization with PLP revealed an interstitial and submeningeal inflammatory infiltrate consisting of neutrophils and monocytes. In all cases, histologic evidence of optic nerve involvement correlated serologically with the presence of circulating anti-PLP antibodies. Control animals had no histopathologic evidence of disease or anti-PLP antibody. In many respects, the observed histopathologic profile of PLP-induced optic neuritis is similar to that associated with human inflammatory demyelinating diseases such as multiple sclerosis (MS). Because optic neuritis frequently is associated with some of the earliest clinical symptoms of MS, the acute nature of optic nerve involvement in this animal model suggests that immune recognition of the myelin PLP may play a significant role in the pathophysiology of optic nerve damage associated with sensitization to CNS-specific antigens.     

Inflammatory demyelination induces axonal injury and retinal ganglion cell apoptosis in experimental optic neuritis

Optic neuritis is an inflammatory disease of the optic nerve that often occurs in patients with multiple sclerosis and leads to permanent visual loss mediated by retinal ganglion cell (RGC) damage. Optic neuritis occurs with high frequency in relapsing-remitting experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, with significant loss of RGCs. In the current study, mechanisms of RGC loss in this model were examined to determine whether inflammation-induced axonal injury mediates apoptotic death of RGCs. RGCs were retrogradely labeled by injection of fluorogold into superior colliculi of 6-7 week old female SJL/J mice. EAE was induced one week later by immunization with proteolipid protein peptide. Optic neuritis was detected by inflammatory cell infiltration on histological examination as early as 9 days after immunization, with peak incidence by day 12. Demyelination occurred 1-2 days after inflammation began. Loss of RGC axons was detected following demyelination, with significant axonal loss occurring by day 13 post-immunization. Axonal loss occurred prior to loss of RGC bodies at day 14. Apoptotic cells were also observed at day 14 in the ganglion cell layer of eyes with optic neuritis, but not in control eyes. Together these results suggest that inflammatory cell infiltration mediates demyelination and leads to direct axonal injury in this model of experimental optic neuritis. RGCs die by an apoptotic mechanism triggered by axonal injury. Potential neuroprotective therapies to prevent permanent RGC loss from optic neuritis will likely need to be initiated prior to axonal injury to preserve neuronal function.     

Application of retinal nerves fiber layer examination--GDx in patients with multiple sclerosis

PURPOSE: The purpose of our study is to evaluate retinal fiber layer thickness with scanning polarymetry laser (GDx), in patients suffering from SM with or without optic nerve symptoms. Multiple sclerosis proceeds to neurodegenerative changes and commonly appears with retrobulbar optic nerve damage. Examination of retinal nerves fiber layer examination with scanning laser polarymetry (GDx) enables to perform quantitative evaluation of retinal nerves fiber layer thickness within the area around the optic nerve disc. It finds application in diagnosis and monitoring of glaucoma, however its usefulness as a tool evaluating optic nerve in multiple sclerosis, has not been proved yet. MATERIALS AND METHODS: Subjects diagnosed with multiple sclerosis (SM) were divided into 2 groups. First group was comprised of subjects, who suffered from at least one episode of retrobulbar neuritis, in at least one eye. Second group was made up of 8 subjects with no history of retrobulbar neuritis. Retinal nerves fiber layer thickness was measured with scanning polarymetry laser (GDx). RESULTS: Symptoms of retinal nerves fiber layer damage, were discovered with GDx significantly more common in first group (70% vs 18.75% accordingly). CONCLUSIONS: Moreover, we stated that evaluation with scanning polarymetry laser might be precious method in discovering retinal nerves fiber layer damage in the course of multiple sclerosis. Presence of defects in retinal nerves fiber layer in patients suffering from multiple sclerosis with no history of retrobulbar neuritis may suggest subclinical damage of optic nerve.     

SIRT1 activation confers neuroprotection in experimental optic neuritis

PURPOSE: Axonal damage and loss of neurons correlate with permanent vision loss and neurologic disability in patients with optic neuritis and multiple sclerosis (MS). Current therapies involve immunomodulation, with limited effects on neuronal damage. The authors examined potential neuroprotective effects in optic neuritis by SRT647 and SRT501, two structurally and mechanistically distinct activators of SIRT1, an enzyme involved in cellular stress resistance and survival. METHODS: Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, was induced by immunization with proteolipid protein peptide in SJL/J mice. Optic neuritis developed in two thirds of eyes with significant retinal ganglion cell (RGC) loss detected 14 days after immunization. RGCs were labeled in a retrograde fashion with fluorogold by injection into superior colliculi. Optic neuritis was detected by inflammatory cell infiltration of the optic nerve. RESULTS: Intravitreal injection of SIRT1 activators 0, 3, 7, and 11 days after immunization significantly attenuated RGC loss in a dose-dependent manner. This neuroprotective effect was blocked by sirtinol, a SIRT1 inhibitor. Treatment with either SIRT1 activator did not prevent EAE or optic nerve inflammation. A single dose of SRT501 on day 11 was sufficient to limit RGC loss and to preserve axon function. CONCLUSIONS: SIRT1 activators provide an important potential therapy to prevent the neuronal damage that leads to permanent neurologic disability in optic neuritis and MS patients. Intravitreal administration of SIRT1 activators does not suppress inflammation in this model, suggesting that their neuroprotective effects will be additive or synergistic with current immunomodulatory therapies.     

实验性变态反应性脑脊髓炎小鼠早期视神经的病理学改变及轴索损伤的研究

目的 观察实验性变态反应性脑脊髓炎(EAE)小鼠早期视神经的病理学动态变化及髓鞘轴索损伤的动态过程,为进一步有效干预性治疗提供理论依据.方法 实验研究.MOG多肽免疫C57BL/6小鼠构建EAE模型;通过形态学观察正常对照组及EAE组小鼠视神经免疫后7、11、15、19 d的病理学变化;免疫组化方法检测正常对照组及EAE组小鼠视神经上述时点正常髓鞘蛋白2、3-环核苷3磷酸二酯酶(CNPase)及轴索损害的标志物β淀粉样前体蛋白(β-APP)蛋白的动态表达.两组间比较采用独立样本的t检验进行显著性检验.结果 EAE组小鼠视神经免疫后7、11、15、19 d分别出现了逐渐加重的炎症反应;正常髓鞘蛋白CNPase的表达分别为34.35±3.72、21.40±1.75、18.10±1.35、10.88±1.00从免疫后11 d起,与正常对照组比较,差异有统计学意义(t=3.16,4.04,5.83,P<0.05);轴索损害的标志物β-APP蛋白的表达量分别为82.15 ±12.35、110.00±12.14、150.95±10.87、182.73 ±9.15与正常对照组比较,差异均有统计学意义(t=2.46,3.71,5.21,7.11;P<0.05).结论 EAE小鼠视神经在不同发病阶段出现不同程度的炎症反应;其轴索损害不完全依赖于脱髓鞘事件.     

Histomorphometric analysis of optic nerve changes in experimental glaucoma

PURPOSE: To assess relative changes in different tissue components of optic nerve and their relationship to nerve fiber loss in the experimental monkey model of glaucoma. METHODS: Chronic intraocular pressure (IOP) elevation was induced by laser trabeculoplasty in the right eye of eight monkeys (Macaca fascicularis). Both experimental right optic nerves and control left optic nerves were studied. Histomorphometric analysis was performed on optic nerve cross-sections using bright field microscopy with camera lucida. Cross-sectional areas of optic nerve tissue components were estimated by point counting. Nerve fiber density was estimated by unbiased random sampling. Nerve fiber number was calculated by multiplying nerve fiber density with neuroglial area. RESULTS: Varying degrees of nerve fiber loss were seen in eight optic nerves with chronic IOP elevation. More than 50% nerve fiber loss was noted in four of eight experimental optic nerves. In these severely affected optic nerves, total optic nerve area was significantly decreased compared with control optic nerves. Among the optic nerve tissue components, only the ratio of myelinated fiber area to total optic nerve area was significantly decreased. The ratio of extraaxonal area to total optic nerve area was significantly increased, whereas the ratio of interfascicular septal area to total optic nerve area did not change significantly. For all optic nerves, differences in nerve fiber count between control and experimental optic nerves showed the strongest correlation with differences in myelinated fiber area, followed by differences in extraaxonal area and total optic nerve area. CONCLUSION: This histomorphometric study suggests the validity of the experimental monkey model of glaucoma in studying changes occurring in the nonaxonal optic nerve tissue components in human glaucomatous optic neuropathy. Glial scar tissue area was significantly increased in optic nerves with severe glaucomatous damage. Although a decrease in total optic nerve area was observed, among the optic nerve tissue components only myelinated nerve fiber area decreased significantly. Myelinated nerve fiber area also showed the strongest association with nerve fiber loss in experimental glaucoma.     

Gadolinium-DTPA-enhanced magnetic resonance imaging in experimental optic neuritis

Magnetic resonance imaging (MRI) with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) was used to investigate disruption of the blood-optic nerve barrier associated with acute autoimmune demyelination. Leakage of Gd-DTPA was seen in the optic nerves and optic chiasm of adult guinea pigs sensitized for acute experimental allergic encephalomyelitis, but not in normal unsensitized animals. This finding occurred as early as 5 to 8 days after antigenic sensitization with the myelin emulsion and before the onset of paralysis or ataxia. Pathologic examination at this early stage of experimental allergic encephalomyelitis showed an absence of demyelination in the optic nerves and optic chiasm, although scant perivascular foci of inflammatory cells were seen. Leakage of Gd-DTPA in the optic nerve before demyelination of this white matter tract illustrates that increased permeability of the blood-optic nerve barrier is an early, if not the initial, event in autoimmune demyelination, and the optic nerve is a common site of central nervous system involvement during the initial phase of acute experimental allergic encephalomyelitis. Findings in this animal model appear comparable with the results of MRI with Gd-DTPA in patients with optic neuritis, and they suggest that disruption of the blood-optic nerve barrier is a common denominator for both disorders of primary demyelination.     

外伤性眼球萎缩眼视神经组织中bcl-2相关死亡基因bad的表达及其意义

目的 探讨外伤性眼球萎缩眼视神经组织中bcl-2相关死亡基因bad表达情况及其意义。 方法 用免疫组织化学的方法观察8只正常对照尸体眼、31只外伤性眼球萎缩眼视神经组织中bad的表达情况。 结果 眼球萎缩眼视神经退行性变表现为视神经髓鞘进行性脱失，神经胶质细胞增生补充。bad表达于正常视神经髓鞘组织及眼球萎缩眼视神经残存髓鞘组织，束间隔及神经胶质细胞中无bad表达。眼球萎缩眼残存的视神经组织较正常视神经组织bad表达量有增高趋势(P＜0.05)；但与眼球萎缩病程长短及导致眼球萎缩的病因之间无直接线性关系(P＞0.05)。 结论 bad可能具有促进外伤性眼球萎缩眼视神经退行性变的作用。 (中华眼底病杂志, 2002, 18: 276-278)     

Antioxidant enzyme suppression of demyelination in experimental optic neuritis

Detoxification of hydrogen peroxide by the antioxidant enzyme catalase suppressed the neurologic manifestations of acute experimental allergic encephalomyelitis (EAE) and prevented death of treated adult strain-13 guinea pigs. The oxygen radical scavenger superoxide dismutase (SOD) delayed the onset of paralysis by one day, but did not prevent death from encephalomyelitis common to most of this group and all untreated animals. Histopathologic analysis of the optic nerves confirmed a statistically significant reduction in demyelination with catalase treatment, but not with SOD. Hydrogen peroxide, and/or its conversion products, discharged by phagocytic mononuclear cells, may play a role in the pathogenesis of demyelination in experimental optic neuritis.     

Gadolinium-DTPA-enhanced magnetic resonance imaging in optic neuropathies

Magnetic resonance imaging (MRI), after intravenous administration of the paramagnetic agent gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), showed enhancement of the optic nerve in 7 of 13 patients with acute optic neuritis. Four of these patients had Gd-DTPA enhancement of the intracranial optic nerve and two had involvement of the optic nerve at the orbital apex, ipsilateral to the eye with visual loss. Gadolinium-DTPA enhancement of both intracranial optic nerves was seen in one of two patients with bilateral retrobulbar neuritis. Two patients with acute radiation-induced optic neuropathy also had Gd-DTPA enhancement of the intracranial optic nerve. The authors recommend MRI with Gd-DTPA as the neuro-diagnostic procedure of choice for visualization of increased permeability of the blood-brain barrier in acute optic neuritis and radiation-induced optic neuropathy.     

Axonal transport reductions in acute experimental allergic encephalomyelitis: qualitative analysis of the optic nerve

In order to determine if changes in axonal transport were different in adult animals with acute experimental allergic encephalomyelitis (EAE), in comparison to juvenile animals with chronic EAE, the effects of this acute demyelinating disorder on axonal transport were examined in the optic nerves of adult strain-13 guinea pigs. Utilizing autoradiographic analysis of silver grain counts, both the fast and slow components of orthograde transport were studied at intervals of thirty minutes, three hours, one day and three days after tritiated leucine injection into the vitreous cavity. In order to determine the contribution of fiber loss in acute EAE, optic nerve fiber density was analyzed from electron micrographs of normal and demyelinated nerves. Animals with acute EAE had a decrease in radioactivity at the lamina retinalis and lamina choroidalis after thirty minutes and three hours, and at the lamina scleralis and foci of demyelination after one and three days. A 16% loss of fibers did not account for as much as a 74% reduction in radioactivity with acute EAE. The global reductions in axonal transport observed in acute EAE animals may contribute to their progressive deterioration and eventual demise by lack of delivery of tubulo-vesicular materials for synaptic transmission, axolemmal proteins for electrogenesis and neurofilamentary components of the cytoskeleton. Moreover, they are unlike the increase of fast axonal transport associated with recovery of physiologic function characteristic of animals with the chronic form of the disease.     

Enhancement and demyelination of the intraorbital optic nerve. Fat suppression magnetic resonance imaging.

Conventional spin-echo magnetic resonance imaging (MRI) of intraorbital optic neuritis is hampered by the adjacent high signal and chemical shift artifact of orbital fat. Frequency-selective saturation pulse MRI reduces these problems and was used to determine its utility in evaluation of intraorbital optic neuritis. Eight consecutive patients with optic neuritis underwent MRI within 1 week of the onset of visual loss. Conventional MRI with T1, proton density, and T2 weighting and frequency-selective saturation pulse MRI with T1, proton density, and T2 weighting were performed. After administration of intravenous gadopentetate dimeglumine, T1-weighted conventional and frequency-selective saturation pulse MRI were performed. Frequency-selective saturation pulse MRI showed gadopentetate dimeglumine enhancement in the intraorbital optic nerve in 7 patients and the intracranial optic nerve in 3 patients. Conventional MRI failed to show optic nerve gadopentetate dimeglumine enhancement in patients with intraorbital lesions, but did show intracranial lesions. Frequency-selective saturation pulse MRI showed bilateral optic nerve enhancement in 3 patients with unilateral visual signs and symptoms. Proton density and T2-weighted conventional MRI of the brain showed no convincing signal aberrations in the optic nerves. In the MRI evaluation of intraorbital optic neuritis: (1) frequency-selective saturation pulse fat suppression MRI is superior to T1-weighted conventional MRI in the detection of gadopentetate dimeglumine enhancement; (2) frequency-selective saturation pulse proton density and T2-weighted MRI is superior to proton density and T2-weighted conventional MRI; (3) frequency-selective saturation pulse MRI showed gadopentetate dimeglumine enhancement as well as proton density/T2-weighted signal aberration in exactly the same portion of the intraorbital optic nerve.     

Optic neuritis in the Landry-Guillain-Barré-Strohl syndrome.

A patient with typical Landry-Guillain-Barré-Strohl syndrome (LG-BS) developed bilateral optic neuritis. Laboratory studies showed hypersensitivity to both central and peripheral nervous tissue myelin. The occurrence of optic neuritis is presumably due to autohypersensitivity to central nervous tissue myelin. The initial lesions of the LG-BS syndrome in the peripheral nerves might have liberated sequestered antigens that cross-reacted with central nervous system myelin.     

Myelin/oligodendrocyte glycoprotein-specific T-cells induce severe optic neuritis in the C57BL/6 mouse

PURPOSE: The optic nerve is a common site of tissue damage in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). To determine the relationship between optic neuritis (ON) and EAE, we examined the incidence of ON in C57BL/6 (B6) mice immunized with a myelin oligodendrocyte/glycoprotein (MOG)-derived peptide or injected with MOG-specific T cells, which are known to induce EAE. METHODS: Mice were immunized with MOG35-55 or MOG40-54 peptides emulsified in complete Freund's adjuvant (CFA). Pertussis toxin (PTX) was injected intraperitoneally 1 day before and after immunization. For disease induction by adoptive transfer of primed cells, donor C57BL/6 mice were received with T-cell blasts (1-6 x 10(6)/mouse). Both EAE and ON were observed by either clinical signs or histology. RESULTS: ON developed in a high proportion of B6 mice treated with either protocol. The most severe inflammation was observed in the adoptively transferred mice. The induced ON was most frequently bilateral. In either actively or adoptively transferred diseases, both association and dissociation of EAE and ON was observed. CONCLUSIONS: Different MOG-specific T-cell subsets might be involved in the pathogenesis of EAE and ON. A better understanding of the pathogenesis of ON after induction by MOG may have important diagnostic and therapeutic implications.