Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: Implications for glaucoma
Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: Implications for glaucoma
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DOI：
10.1073/pnas.041609498
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发表时间：
2001-03-13
影响因子：
11.1
通讯作者：
Schwartz, M
中科院分区：
文献类型：
--
作者：
Schori, H;Kipnis, J;Schwartz, M
我们的研究小组最近证明，针对中枢神经系统相关髓鞘抗原的自身免疫T细胞保护神经元免受继发性变性。我们进一步表明，已知抑制实验性自身免疫性脑脊髓炎的合成肽共聚物1（Cop-1）可以安全地替代天然髓鞘抗原，用于被动和主动免疫以保护受损的视神经。在这里，我们试图确定是否类似的免疫是保护视网膜神经节细胞损失所造成的直接生化损伤，例如，谷氨酸盐（一个主要的调解人的变性在急性和慢性视神经损伤）和高眼压的大鼠模型。被动免疫与T细胞反应髓鞘碱性蛋白或主动免疫与髓鞘少突胶质细胞糖蛋白衍生肽，虽然视神经损伤后的神经保护，对小鼠和大鼠的谷氨酸毒性是无效的。相比之下，在用完全弗氏佐剂中乳化的Cop-1免疫10天前的小鼠中，在注射谷氨酸盐的视网膜中每平方毫米存活的视网膜神经节细胞的数量显著大于注射相同佐剂中的PBS的小鼠（分别为2，133 +/-270和1，329 +/-121，平均值+/- SEM; P < 0.02）。当小鼠在谷氨酸注射当天免疫时观察到类似的模式（1，777 +/- 101与1，414 +/- 36; P < 0.05），但当它们在48小时后免疫时则没有。这些发现表明，保护免受谷氨酸毒性需要通过与髓鞘相关的抗原不同的抗原来增强免疫系统。Cop-1的使用显然绕过了这种抗原特异性屏障。在模拟青光眼的大鼠高眼压模型中，用Cop-1免疫使视网膜神经节细胞损失从27.8% +/-6.8%显著降低至4.3%+/-1.6%，而不影响眼内压。这项研究可能为青光眼的治疗指明了方向，青光眼是一种通常与眼内压升高相关的视神经神经退行性疾病，以及谷氨酸是主要参与者的急性和慢性退行性疾病。
Our group recently demonstrated that autoimmune T cells directed against central nervous system-associated myelin antigens protect neurons from secondary degeneration. We further showed that the synthetic peptide copolymer 1 (Cop-1), known to suppress experimental autoimmune encephalomyelitis, can be safely substituted for the natural myelin antigen in both passive and active immunization for neuroprotection of the injured optic nerve. Here we attempted to determine whether similar immunizations are protective from retinal ganglion cell loss resulting from a direct biochemical insult caused, for example, by glutamate (a major mediator of degeneration in acute and chronic optic nerve insults) and in a rat model of ocular hypertension. Passive immunization with T cells reactive to myelin basic protein or active immunization with myelin oligodendrocyte glycoprotein-derived peptide, although neuroprotective after optic nerve injury, was ineffective against glutamate toxicity in mice and rats. In contrast, the number of surviving retinal ganglion cells per square millimeter in glutamate-injected retinas was significantly larger in mice immunized 10 days previously with Cop-1 emulsified in complete Freund's adjuvant than in mice injected with PBS in the same adjuvant (2,133 +/- 270 and 1,329 +/- 121, respectively, mean +/- SEM; P < 0.02). A similar pattern was observed when mice were immunized on the day of glutamate injection (1,777 +/- 101 compared with 1,414 +/- 36; P < 0.05), but not when they were immunized 48 h later. These findings suggest that protection from glutamate toxicity requires reinforcement of the immune system by antigens that are different from those associated with myelin. The use of Cop-1 apparently circumvents this antigen specificity barrier. In the rat ocular hypertension model, which simulates glaucoma, immunization with Cop-1 significantly reduced the retinal ganglion cell loss from 27.8% +/- 6.8% to 4.3 % +/- 1.6 %, without affecting the intraocular pressure. This study may point the way to a therapy for glaucoma, a neurodegenerative disease of the optic nerve often associated with increased intraocular pressure, as well as for acute and chronic degenerative disorders in which glutamate is a prominent participant.