Opinion
Dual action of glatiramer acetate (Cop-1) in the treatment of CNS autoimmune and neurodegenerative disorders

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Abstract

Protective autoimmunity is the body's defense mechanism against destructive self-compounds such as those commonly associated with neurodegenerative disorders. Autoimmune disease and neurodegenerative disorders can thus be viewed as two extreme manifestations of the same process. Therefore, when designing therapy, it is important to avoid an approach that will cure the one by invoking the other. One way to stop, or at least slow down, the progression of neurodegeneration without risking development of an autoimmune disease is by boosting protective autoimmunity in a well-controlled way. Copolymer 1 (Cop-1), an approved drug for the treatment of multiple sclerosis, can be used as a treatment for autoimmune diseases and as a therapeutic vaccine for neurodegenerative diseases. We propose that the protective effect of Cop-1 vaccination is obtained through a well-controlled inflammatory reaction, and that the activity of Cop-1 in driving this reaction derives from its ability to serve as a ‘universal antigen’ by weakly activating a wide spectrum of self-reactive T cells.

Section snippets

Autoimmune neuroprotection – a physiological self-repair mechanism

In certain strains of rats, passive transfer of autoimmune T cells reactive to myelin-related self-antigens induces a transient autoimmune syndrome known as experimental autoimmune encephalomyelitis (EAE) 26., 27.. If these strains of rats are subjected either to partial crush injury of the optic nerve or to contusive injury of the spinal cord, the autoimmune cell transfer not only induces EAE but also confers neuroprotection by reducing secondary degeneration of the damaged neural tissue 21.,

Cop-1 in autoimmune disease

Cop-1 (Copaxone®) is a synthetic amino acid polymer (4.7–11 kDa) composed of four amino acids (l-alanine, l-lysine, l-glutamic acid and l-tyrosine) in a defined molar ratio 37., 38.. It was originally synthesized to mimic the activity of myelin basic protein (MBP) by inducing EAE in laboratory animals [39], but was found to be non-encephalitogenic and even to suppress MBP-induced EAE [40]. Cop-1 blocks chronic-relapsing EAE induced in a (SJL/J × BALB/c) F1 mouse model by application of mouse

Low-affinity self-reacting Tcells are activated by Cop-1: a ‘safe’ therapeutic vaccine for neurodegenerative disorders

An initial assumption was that Cop-1, by crossreacting with MBP or other components of myelin, might enable Cop-1-specific T cells to recognize the damaged tissue, accumulate there, and undergo activation resulting in neuroprotection [35]. However, more-recent studies have shown that T cells reactive to Cop-1 do not proliferate when exposed to myelin proteins [48]. After partial crush injury of the rat optic nerve, myelin epitopes are exposed at the site of injury. Following injury, peripheral

Cop-1 as an immunomodulator in cases of inflammation

As discussed above, Cop-1 provides effective treatment both for MS [57] and for injuries of the CNS 35., 36.. The question then arises: do the two types of disorders have common features that could explain why the same compound, when administered according to a suitable therapeutic regimen, is effective in both? Or do the unique features of Cop-1 as a weak universal self-antigen make it suitable for different indications? The principal common characteristic of the two conditions is

Differential modes of Cop-1 administration in patients with MS or with CNS injury

If Cop-1 acts as a universal antigen, questions arise in connection with the optimal therapeutic regimens of Cop-1 for different conditions. Should patients with autoimmune diseases be treated in the same way as patients with acute or chronic neurodegenerative disorders? In the case of autoimmune disease, where the regulation of autoimmunity is malfunctioning, there is a need to shut off the autoimmune clones. By contrast, in the case of acute CNS injury or chronic neurodegenerative disorders

Concluding remarks

We suggest that the optimal application of Cop-1 for the treatment of neurodegenerative diseases is by vaccination in order to activate the weakly self-reactive Th1 cells in a well-regulated way. According to our perception of autoimmunity, the regimen for Cop-1 administration in individuals with autoimmune disease (daily injection) differs from that required for treatment after CNS injury. Future studies should be aimed at establishing the optimal regimen for Cop-1 administration in

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