Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Copolymer 1 (Copaxone) is a mixture of synthetic peptides composed of four amino acids. It has been shown to alter positively the natural history of multiple sclerosis by both reducing the relapse rate and affecting disability. A recently completed, large-scale, phase III, multicenter, double-blind study confirmed the therapeutic benefit shown in previous pilot studies. Side effects were mild and the daily subcutaneous treatment was well tolerated. Laboratory studies have shown that copolymer 1 prevents or modifies experimental allergic encephalomyelitis in several mammalian species. It induces immunologic suppressor cells, which are deficient in multiple sclerosis, and competitively inhibits the effect of central nervous system myelin antigens, thought to be important in the pathogenesis of multiple sclerosis. Copolymer 1 joins interferon beta in ushering in a new era of well-tolerated treatments for multiple sclerosis.
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PMID:A review of the clinical efficacy profile of copolymer 1: new U.S. phase III trial data. 896 18

The synthetic random amino acid copolymer Copolymer 1 (Cop 1, Copaxone, glatiramer acetate) suppresses experimental autoimmune encephalomyelitis, slows the progression of disability, and reduces relapse rate in multiple sclerosis (MS). Cop 1 binds to various class II major histocompatibility complex (MHC) molecules and inhibits the T cell responses to several myelin antigens. In this study we attempted to find out whether, in addition to MHC blocking, Cop 1, which is immunologically cross-reactive with myelin basic protein (MBP), inhibits the response to this autoantigen by T cell receptor (TCR) antagonism. Two experimental systems, "prepulse assay" and "split APC assay," were used to discriminate between competition for MHC molecules and TCR antagonism. The results in both systems using T cell lines/clones from mouse and human origin indicated that Cop 1 is a TCR antagonist of the 82-100 epitope of MBP. In contrast to the broad specificity of the MHC blocking induced by Cop 1, its TCR antagonistic activity was restricted to the 82-100 determinant of MBP and could not be demonstrated for proteolipid protein peptide or even for other MBP epitopes. Yet, it was shown for all the MBP 82-100-specific T cell lines/clones tested that were derived from mice as well as from an MS patient. The ability of Cop 1 to act as altered peptide and induce TCR antagonistic effect on the MBP p82-100 immunodominant determinant response elucidates further the mechanism of Cop 1 therapeutic activity in experimental autoimmune encephalomyelitis and MS.
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PMID:Copolymer 1 acts against the immunodominant epitope 82-100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. 989 85

The activity of copolymer 1 (Cop 1, Copaxone, glatiramer acetate) in suppressing experimental autoimmune encephalomyelitis (EAE) and in the treatment of multiple sclerosis patients when injected parenterally has been extensively demonstrated. In the present study we addressed the question of whether Cop 1 can induce oral tolerance to EAE similar to myelin basic protein (MBP). We now have demonstrated that oral Cop 1 inhibited EAE induction in both rats and mice. Furthermore, oral Cop 1 was more effective than oral MBP in suppressing EAE in rats. The beneficial effect of oral Cop 1 was found to be associated with specific inhibition of the proliferative and Th1 cytokine secretion responses to MBP of spleen cells from Cop 1-fed mice and rats. In all of these assays, oral Cop 1 was more effective than oral MBP. The tolerance induced by Cop 1 could be adoptively transferred with spleen cells from Cop 1-fed animals. Furthermore, Cop 1-specific T cell lines, which inhibit EAE induction in vivo, could be isolated from the above spleen cells. These T cell lines secrete the anti-inflammatory cytokines IL-10 and transforming growth factor type beta, but not IL-4, in response to both Cop 1 and MBP. In conclusion, oral Cop 1 has a beneficial effect on the development of EAE that is associated with down-regulation of T cell immune responses to MBP and is mediated by Th2/3 type regulatory cells. These results suggest that oral administration of Cop 1 may modulate multiple sclerosis as well.
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PMID:Immunomodulation of experimental autoimmune encephalomyelitis by oral administration of copolymer 1. 1009 37

Copolymer 1 (Cop 1, Copaxone) is a synthetic amino acid copolymer effective in suppression of experimental allergic encephalomyelitis (EAE). The suppressive effect of Cop 1 in EAE is not restricted to a certain species, disease type or encephalitogen used for EAE induction. In phases II and III clinical trials Cop 1 was found to slow progression of disability and reduce the relapse rate in exacerbating-remitting multiple sclerosis (MS) patients. To extend this concept we have more recently shown that a similar approach is possible in the case of myasthenia gravis. We used two myasthenogenic T cell epitopes of the human acetylcholine receptor alpha-subunit and demonstrated that they are capable of triggering peripheral blood lymphocytes of the majority (>80%) of myasthenic patients tested. Both single amino acid analogs, and a dual analog composed of the tandemly arranged two single amino acid analogs were able to inhibit in vitro proliferative responses of T cell lines, and in vivo priming of lymph node cells. The dual analog inhibited experimental autoimmune myasthenia gravis even when the mice were treated fourteen days after the injection of the pathogenic T cell line.
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PMID:The concept of specific immune treatment against autoimmune diseases. 1061 24

We sought to determine whether combinations of glatiramer acetate and parenteral or ingested type I interferon were synergistic in experimental autoimmune encephalomyelitis. Glatiramer acetate, subcutaneous murine interferon-alpha, or ingested murine interferon-alpha individually improved clinical scores. In contrast, glatiramer acetate in conjunction with either subcutaneous or ingested interferon-alpha did not improve clinical scores compared with control. These data suggest that clinical trials designed to test a possible synergistic effect of glatiramer acetate and type I interferon in humans should be designed to detect possible adverse effects of this combination of immunomodulatory agents.
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PMID:Combination therapy with glatiramer acetate (copolymer-1) and a type I interferon (IFN-alpha) does not improve experimental autoimmune encephalomyelitis. 1063 13

Copolymer 1 (Cop 1, Copaxone) is a synthetic amino acid copolymer effective in suppression of experimental allergic encephalomyelitis (EAE). The suppressive effect of Cop 1 in EAE is not restricted to a certain species, disease type or encephalitogen used for EAE induction. In phase II and III clinical trials, Cop 1 was found to slow the progression of disability and reduce the relapse rate in exacerbating-remitting multiple sclerosis (MS) patients. In vivo and in vitro studies suggest that the mechanism for Cop 1 activity in EAE and MS involves, as an initial step, the binding of Cop 1 to MHC class II molecules. This binding results in competition with myelin antigens for T-cell activation, both at the MHC and T-cell receptor levels and in induction of specific suppressor cells of the Th2 type. As an antigen-specific intervention, Cop 1 has the advantage of reduced probability for long-term damage to the immune system, and is thus a safe and effective novel therapeutic approach to MS. It also serves to illustrate the new concept of a drug/vaccine specific for a single autoimmune disease. Indeed, we have used a similar approach for myasthenia gravis. Myasthenia gravis (MG) and its experimental animal model, experimental autoimmune MG (EAMG), are immune disorders characterized by circulating antibodies and lymphocyte autoreactivity to nicotinic acetylcholine receptor (AChR). We utilized peptides representing different sequences of the human acetylcholine receptor alpha-subunit to study the role of T cells in the initiation, development and immunomodulation of myasthenia gravis. Here we summarize our studies over the last decade on T cells specific to 'myasthenogenic' epitopes of the alpha-subunit of the human acetylcholine receptor and their relevance for myasthenia gravis.
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PMID:Specific vaccines against autoimmune diseases. 1064 86

This study addresses the issue of the effect of immunomodulating therapies in the target organ-the central nervous system (CNS)-in the case of multiple sclerosis. Copolymer 1 (Cop 1, Copaxone, glatiramer acetate), an approved drug for the treatment of multiple sclerosis, is a potent inducer of Th2 regulatory cells in both mice and humans. Highly reactive Cop 1-specific T cell lines that secrete IL-4, IL-5, IL-6, IL-10, and transforming growth factor-beta in response to Cop 1 and crossreact with myelin basic protein (MBP) at the level of Th2 cytokine secretion were established from both brains and spinal cords of Cop 1-treated mice. In contrast, no reactivity to the control antigen lysozyme could be obtained in lymphocytes isolated from CNS of mice injected with lysozyme. Adoptively transferred labeled Cop 1-specific suppressor cells were found in brain sections 7 and 10 days after their injection to the periphery, whereas lysozyme-specific cells were absent in the CNS. Hence, Cop 1-induced Th2 cells cross the blood-brain barrier and accumulate in the CNS, where they can be stimulated in situ by MBP and thereby exert therapeutic effects in the diseased organ. This therapeutic effect was manifested, in brains of experimental autoimmune encephalomyelitis-induced mice, by a decrease in the inflammatory cytokine interferon-gamma and by secretion of the anti-inflammatory cytokine IL-10 in response to the autoantigen MBP.
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PMID:Specific Th2 cells accumulate in the central nervous system of mice protected against experimental autoimmune encephalomyelitis by copolymer 1. 1102 47

Free radicals including peroxynitrite are induced in Multiple Sclerosis (MS). Antioxidant and peroxynitrite inhibitor uric acid (UA), suppresses the MS animal model experimental autoimmune encephalomyelitis (EAE). MS patients have lower average serum UA than controls. An inverse relationship exists between MS and gout Glatiramer acetate (GA) suppresses EAE and is beneficial in relapsing MS. We investigated serum UA changes during open-label treatment of relapsing MS with GAA. Ten patients (six females, four males, aged 19 to 39 years, mean age 32 years) completed 6 months of GAA (Copaxone 20 mg s.c daily). Of these, nine completed 12 months. After 6 months on GAA, serum UA (normal, 173359 micromol/ml for women, 258-491 micromol/ml for men) increased in nine and marginally decreased (302 to 300 micromol/ml) in a single patient. Mean UA significantly increased from 240 to 303 micromol/ml (P=0.0014). At 12 months, UA remained significantly higher than at start (P=0.006) decreasing in only one patient. In contrast, we found no significant UA changes after 6 and 12 months of treatment in 21 MS patients treated with interferon beta1-a (Avonex), or in 11 treated with interferon beta1-a (Rebif), or in five placebo-treated controls. Increasing UA, a natural inhibitor of free radicals, may represent a mechanism of action of glatiramer acetate in MS.
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PMID:Increase in serum levels of uric acid, an endogenous antioxidant, under treatment with glatiramer acetate for multiple sclerosis. 1121 32

Copolymer-1 (Copaxone or COP) inhibits experimental allergic encephalomyelitis and has beneficial effects in multiple sclerosis. There is presently no practical in vitro assay for monitoring the immunological effects of COP. We used an automated, computer-assisted enzyme-linked immunoadsorbent spot assay for detecting COP-induced interferon-gamma (IFN-gamma)- and interleukin-4 (IL-4)-producing cells and a standard proliferation assay to assess the immunological response to COP in peripheral blood mononuclear cells from 20 healthy donors, 20 untreated multiple sclerosis patients and 20 COP-treated multiple sclerosis patients. Compared with untreated and healthy controls, COP-treated patients showed (i) a significant reduction of COP-induced proliferation; (ii) a positive IL-4 Elispot response mediated predominantly by CD4 cells after stimulation with a wide range of COP concentrations; and (iii) an elevated IFN-gamma response partially mediated by CD8 cells after stimulation with high COP concentrations. All three effects were COP-specific as they were not observed with the control antigens, tuberculin-purified protein or tetanus toxoid. The COP-induced changes were consistent over time and allowed correct identification of COP-treated and untreated donors in most cases. We propose that these criteria may be helpful to monitor the immunological response to COP in future clinical trials.
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PMID:Treatment of multiple sclerosis with Copaxone (COP): Elispot assay detects COP-induced interleukin-4 and interferon-gamma response in blood cells. 1128 71

Glatiramer acetate (Copaxone) is a novel preparation of synthetic peptides composed of four amino acids. Laboratory studies have shown that it prevents, or modifies, experimental allergic encephalomyelitis, the animal model for multiple sclerosis (MS), in several mammalian species. Its mode of action has not been fully elucidated but it is known to induce suppresser T-cells, known to be deficient in MS, and competitively inhibits the effect of CNS myelin antigens, thought to be important in the pathogenesis of MS, through MHC blockade. Controlled clinical trials have shown it to improve the natural history of MS by reducing both the relapse rate and the resultant disability. GA shows similar efficacy to interferon-beta (IFN-beta) but with fewer systemic side-effects and appears to be better tolerated by patients. It has thus justified its place in the new era of disease-modifying treatments for MS. While the evidence suggests GA should be considered as first-line therapy in selected patients, its differing mechanism of action also gives patients and doctors the option of an alternative agent when the efficacy of IFN-beta is waning or side-effects predominate.
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PMID:Glatiramer acetate (Copaxone). 1150 Dec 29


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