Antigenic specificity of immunoprotective therapeutic vaccination for glaucoma
Antigenic specificity of immunoprotective therapeutic vaccination for glaucoma
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DOI：
10.1167/iovs.03-0080
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发表时间：
2003-08-01
影响因子：
4.4
通讯作者：
Schwartz, M
中科院分区：
文献类型：
--
作者：
Bakalash, S;Kessler, A;Schwartz, M
目的.目的探讨视网膜神经节细胞（retinal ganglion cells，RGCs）抗高眼压（high intraocular pressure，lop）死亡的免疫保护机制的抗原特异性。用氩激光光凝大鼠巩膜外静脉和角膜缘丛，引起单侧眼压升高。用醋酸格拉替雷（Cop-1，一种合成共聚物）或髓磷脂衍生肽或葡萄膜生成肽免疫高IOP大鼠。当使用类固醇药物甲基强的松龙时，每隔一天腹腔注射一次，持续12天。用存在于轴突中的髓磷脂衍生肽进行疫苗接种未能保护RGCs免受高IOP引起的死亡。与此相反，IOP诱导的RGC损失减少接种R16，一种肽衍生自interphotoreceptor类维生素A结合蛋白，免疫显性抗原驻留在眼睛。对IOP诱导的RGC损失的保护的益处超过了在易感大鼠品系中短暂发展的双相实验性自身免疫性葡萄膜炎（EAU）的成本。甲泼尼龙治疗缓解了疾病症状，但导致RGCs进一步丧失。Cop-1疫苗对EAU耐药株和敏感株均有效。为了使受损的神经元受益，免疫神经保护应该针对存在于损伤部位的免疫显性抗原。在高IOP的大鼠模型中，RGCs可以受益于用源自在眼睛中免疫显性的蛋白质而不是髓鞘相关蛋白质的肽进行的疫苗接种。这表明IOP诱导的RGC损失中的原发性变性部位在眼睛中。Cop-1疫苗接种显然绕过了位点特异性屏障，提供了保护，而没有诱导自身免疫性疾病的风险。
PURPOSE. To investigate the antigenic specificity of the immune neuroprotective mechanism that can protect retinal ganglion cells (RGCs) against death caused by high intraocular pressure (lop).METHODS. A unilateral increase in IOP was induced in rats by argon laser photocoagulation of the episcleral veins and limbal plexus. Rats with high IOP were immunized with glatiramer acetate (Cop-1, a synthetic copolymer) or with myelin-derived or uveitogenic peptides. When the steroid drug methylprednisolone was used, it was administered intraperitoneally every other day for 12 days.RESULTS. Vaccination with myelin-derived peptides that reside in the axons failed to protect RGCs from death caused by high IOP. In contrast, IOP-induced RGC loss was reduced by vaccination with R16, a peptide derived from interphotoreceptor retinoid-binding protein, an immunodominant antigen residing in the eye. The benefit of protection against IOP-induced RGC loss outweighed the cost of the monophasic experimental autoimmune uveitis (EAU) that transiently developed in a susceptible rat strain. Treatment with methylprednisolone alleviated the disease symptoms, but caused further loss of RGCs. Cop-1 vaccination was effective in both EAU-resistant and EAU-susceptible strains.CONCLUSIONS. To benefit damaged neurons, immune neuroprotection should be directed against immunodominant antigens that reside in the site of damage. In a rat model of high IOP, RGCs can benefit from vaccination with peptides derived from proteins that are immunodominant in the eye but not from myelin-associated proteins. This suggests that the site of primary degeneration in IOP-induced RGC loss is in the eye. Cop-1 vaccination apparently circumvents the site-specificity barrier and provides protection without risk of inducing autoimmune disease.