T-cell-based vaccination for morphological and functional neuroprotection in a rat model of chronically elevated intraocular pressure

Abstract

Acute or chronic glaucoma is often associated with an increase in intraocular pressure (IOP). In many patients, however, therapeutic pressure reduction does not halt disease progression. Neuroprotection has been proposed as a complementary therapeutic approach. We previously demonstrated effective T-cell-based neuroprotection in experimental animals vaccinated with the synthetic copolymer glatiramer acetate (copolymer-1, Cop-1), a weak agonist of self-antigens. This study was undertaken to test different routes and modes of vaccination with Cop-1 as treatment modalities for protection against retinal ganglion cell (RGC) death caused by chronic elevation of IOP in rats, and to determine whether anatomical neuroprotection is accompanied by functional neuroprotection. In a chronic model of unilaterally high IOP, Cop-1 vaccination, with or without an adjuvant, protected rats against IOP-induced loss of RGCs by eliciting a systemic T-cell-mediated response capable of cross-reacting with self-antigens residing in the eye. In rats deprived of T cells, Cop-1 (unlike treatment with alpha2-adrenoreceptor agonists) was not protective of RGCs, substantiating the contention that its beneficial effect is not conferred directly but is T-cell-mediated. Pattern electroretinography provided evidence of functional protection. Thus, vaccination with adjuvant-free Cop-1 can protect RGCs from the consequences of elevated IOP in rats. This protection is manifested both morphologically and functionally. These findings can be readily implemented for the development of a therapeutic vaccination to arrest the progression of glaucoma.

Copper-Zinc Superoxide Dismutase (SOD1) Is Released by Microglial Cells and Confers Neuroprotection against 6-OHDA Neurotoxicity

“…Therefore, the identification of other microglia-released factors involved in neuroprotection will likely contribute to explaining why other types of neurotoxicity (a shift of CGNs to nondepolarizing con-ditions or excitotoxicity) are significantly reverted by MCM, but not by exogenous SOD1. Differences in SOD1 neuroprotection against different toxic stimuli are in line with previous works that have or have not found neuroprotective effects of SOD1 in nonconditioned media, sometimes using very high amounts of exogenously added protein [60,61,62,63,64,65,66]. To further complicate this situation, it has to be considered that SOD1 may act on target cells both through its catalytic activity and through receptor interaction [46,47].…”

“…While superoxide dismutase is usually released by cells in its SOD3 isoform [58,59], also SOD1 is released by several cell lines [31,32,33,34]. Moreover, high concentrations of SOD1 may protect neurons from some toxic insults [60,61,62,63,64,65,66]. Here we show that SOD1 is produced and released by microglia and is a neuroprotective factor against 6-OHDA neurotoxicity in CGNs.…”

Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1

“…A single injection of GA is protective in acute models of CNS insults (13,15), whereas in chronic models occasional boosting rather than daily is required for a long-lasting protective effect (14). In a model of chronically elevated intraocular pressure, for example, weekly administration of adjuvant-free GA was found to result in neuroprotection (19). The neuroprotective effect of GA has been attributed in part to production of brainderived neurotrophic factor (26).…”

“…The GA was repeatedly injected without adjuvant and according to a regimen similar to that used to evoke neuroprotection in a model of chronic elevation of intraocular pressure (19); a daily injection was ineffective in this model.…”

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

“…They found that vaccination with this agent can protect RGCs from the consequences of elevated IOP in rats. 90 Therefore, T-cell-mediated responses may participate in glaucomaassociated optic neuropathy. On the basis of the use of DNA microarrays, Mao et al 91 had previously looked for genes specifically involved in human T-cell activation, and one of them was WDR36, which highly co-regulated with interleukin-2.…”