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Abstract #19150 Published in IGR 3-1
Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma
Schori H; Kipnis J; Yoles E; Wolde Mussie E; Ruiz G; Wheeler LA; Schwartz MProceedings of the National Academy of Sciences of the United States of America 2001; 98: 3398-3403
The authors' group recently demonstrated that autoimmune T cells directed against central nervous system-associated myelin antigens protect neurons from secondary degeneration. They 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 ten days previously with Cop-1 emulsified in complete Freund's adjuvant than in mice injected with PBS in the same adjuvant (2133 ± 270 and 1329 ± 121, respectively, mean ± SEM; p < 0.02). A similar pattern was observed when mice were immunized on the day of glutamate injection (1777 ± 101 compared with 1414 ± 36; p < 0.05), but not when they were immunized 48 hours 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.
Dr H. Schori, Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel
Classification:
11.8 Neuroprotection (Part of: 11 Medical treatment)
