Trends in Molecular Medicine
OpinionDual action of glatiramer acetate (Cop-1) in the treatment of CNS autoimmune and neurodegenerative disorders
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
References (64)
- et al.
Degeneration of spared axons following partial white matter lesion: implications for optic nerve neuropathies
Exp. Neurol.
(1998) Diffuse prolonged depression of cerebral oxidative metabolism following concussive brain injury in the rat: a cytochrome oxidase histochemistry study
Brain Res.
(1991)Genetics of rat neuroinflammation
J. Neuroimmunol.
(2000)Bromocriptine in rheumatic and autoimmune diseases
Semin. Arthritis Rheum.
(2001)- et al.
Multiple sclerosis and central nervous system demyelination
J. Autoimmun.
(1999) Autoimmune T cells as potential neuroprotective therapy for spinal cord injury
Lancet
(2000)- et al.
Protective autoimmunity: regulation and prospects for vaccination after brain and spinal cord injuries
Trends Mol. Med.
(2001) - et al.
Autoimmunity can benefit self-maintenance
Immunol. Today
(2000) Oral tolerance: immune mechanisms and the generation of Th3-type TGF-β-secreting regulatory cells
Microbes Infect.
(2001)Copolymer 1 inhibits chronic relapsing experimental allergic encephalomyelitis induced by proteolipid protein (PLP) peptides in mice and interferes with PLP-specific T cell responses
J. Neuroimmunol.
(1996)
Bystander suppression of experimental autoimmune encephalomyelitis by T cell lines and clones of the Th2 type induced by copolymer 1
J. Neuroimmunol.
Studies on the mechanism and specificity of the effect of the synthetic random copolymer GLAT on graft-versus-host disease
Immunol. Lett.
Characterization of T cell lines derived from glatiramer-acetate- treated multiple sclerosis patients
J. Neuroimmunol.
Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes
Immunol. Today
Glia–T cell dialogue
J. Neuroimmunol.
Superantigen presenting capacity of human astrocytes
J. Neuroimmunol.
Antigen and superantigen presentation in the human CNS
J. Neuroimmunol.
The link between excitotoxic oligodendroglial death and demyelinating diseases
Trends Neurosci.
Neurodegenerative disorders: the role of peroxynitrite
Brain Res. Rev.
Nitric oxide, mitochondria and neurological disease
Biochim. Biophys. Acta
Experimental neurobiology of central nervous system trauma
Crit. Rev. Neurobiol.
Excitotoxicity and neurodegeneration in amyotrophic lateral sclerosis
Clin. Neurosci.
Excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis
Adv. Neurol.
Beyond intraocular pressure: neuroprotective strategies for future glaucoma therapy
Optom. Vis. Sci.
Mitochondrial dysfunction in Parkinson's disease
Biochem. Soc. Symp.
Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences
Curr. Opin. Neurol.
Acute neuronal apoptosis in a rat model of multiple sclerosis
J. Neurosci.
Axon damage and repair in multiple sclerosis
Philos. Trans. R. Soc. Lond. B Biol. Sci.
Oral toleragens in rheumatoid arthritis
Curr. Opin. Invest. Drugs
Intense immune suppression for systemic lupus – the role of hematopoietic stem cells
J. Clin. Immunol.
Immunosuppressive applications of PHA and other plant mitogens
Cancer Biother. Radiopharm.
Therapeutic inhibition of the complement system. Y2K update
Front. Biosci.
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2013, Progress in Retinal and Eye ResearchCitation Excerpt :Moreover, evoking protective autoimmunity can be achieved by active immunization with the self-antigen or passive vaccination with activated T-cells directed against the self-antigen (Hauben et al., 2000, 2003; Moalem et al., 1999; Schori et al., 2001; Schwartz, 2001b). Since autoimmune diseases and neurodegenerative processes can be seen as two manifestations of the same process (Kipnis and Schwartz, 2002), T-cell therapy, as well as active vaccination with self-antigen, must be well controlled to avoid autoimmune disease (Schwartz, 2001a). It was suggested that natural autoantibodies, mostly IgMs may counteract destructive autoimmune processes by suppressing cross-reactions of autoreactive clones with self-antigens by masking their antigenic components (Shoenfeld and Toubi, 2005).
Chronic mild stress eliminates the neuroprotective effect of Copaxone after CNS injury
2013, Brain, Behavior, and ImmunityGlatiramer acetate reverts stress-induced alterations on adult neurogenesis and behavior. Involvement of Th1/Th2 balance
2012, Brain, Behavior, and ImmunityCitation Excerpt :Reports indicate that MS patients treated with GA initially show a Th1-type response, which later switches towards Th2 (Farina et al., 2001). Thus, it was propose that a short pretreatment leads to a weak Th1 response that may attenuate neurodegeneration, whereas prolonged pretreatment leads to a Th2 response that may lessen autoimmune disease (Kipnis and Schwartz, 2002). In this context, it was demonstrated that immune treatment with CNS-related peptide that activate weakly self-reactive T cells can ameliorate depressive behavior induced by CMS in rats.