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)

This review article summarises the initial preclinical studies as well as the different stages of clinical trials in multiple sclerosis (MS) with Copolymer 1 (Cop 1), recently denoted glatiramer acetate. Experimental studies on autoimmune encephalomyelitis (EAE), the animal model of MS, as well as studies on the mechanism of action in both animals and humans are discussed. The review describes the early clinical trials which were followed by Phase II and III trials, culminating in FDA approval in 1996 for the treatment of relapsing-remitting MS. The accumulated experience with glatiramer acetate indicates that its efficacy is apparently increased as a function of usage time while the favourable side effect profile is sustained. MRI studies revealed that treatment with glatiramer acetate resulted in a significant reduction of gadolinium (Gd)-enhancing lesions. Ongoing clinical trials which might extend its usage or change its mode of delivery are also described. Glatiramer acetate appears to be a treatment of choice for the relapsing-remitting type of MS.
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PMID:Glatiramer acetate in the treatment of multiple sclerosis. 1158 66

Oral tolerance to myelin basic protein (MBP) is an effective antigen-specific method to suppress experimental allergic encephalomyelitis (EAE). Glatiramer acetate [copolymer 1 (Cop1)] is a synthetic copolymer designed to mimic MBP which suppresses EAE, is used parenterally to treat multiple sclerosis (MS) and is being tested orally for efficacy in MS. We investigated the immunologic properties of Cop1 to determine the degree to which its effects were antigen specific using MBP TCR transgenic mice. Immunization of MBP TCR transgenic mice fed Cop1, MBP or MBP Ac1-11 resulted in decreased proliferation, and IL-2, IL-6 and IFN-gamma production, and increased secretion of IL-10 and transforming growth factor (TGF)-beta in Cop1-fed animals. IFN-gamma was decreased, and IL-10 and TGF-beta were increased in non-immunized mice fed Cop1 and stimulated in vitro with MBP. No such effects were observed in ovalbumin TCR transgenic mice. To determine if the effects of Cop1 were specific to MBP TCR-bearing cells, MBP TCR transgenic Rag2(-/-) mice were immunized and re-stimulated in vitro with Cop1. We found a marked increase in IL-4 and similar increases in IL-4 after feeding Cop1. In disease models, feeding Cop1 suppressed EAE in MBP TCR transgenic mice, (PL/J x SJL)F(1) mice, and in myelin oligodendrocyte glycoprotein-induced EAE in NOD mice. Oral Cop1 had no effect on collagen-induced arthritis. These results demonstrate that Cop1 is active orally in an antigen-specific fashion, and may function as an altered peptide ligand for MBP-specific TCR-bearing cells by decreasing pro-inflammatory cytokines (IFN-gamma) and increasing anti-inflammatory cytokines (IL-4, IL-10 and TGF-beta).
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PMID:Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines. 1180 32

Mucosal administration of copolymer 1 (Cop 1, Copaxone(R), glatiramer acetate) suppresses experimental autoimmune encephalomyelitis (EAE), and is currently tested for its efficacy in the treatment of multiple sclerosis (MS). Here we demonstrate that oral treatment with Cop 1 induces, in mice, specific Th2 cells in the central nervous system (CNS), as manifested by their isolation from brains of actively sensitized Cop 1-fed mice, as well as, by the localization of orally induced Cop 1 specific suppressor cells in the brain, after their passive transfer to the periphery. Feeding with Cop 1 results in the accumulation in the CNS of cells that secrete Th2 cytokines in response to either Cop 1 or the autoantigen myelin basic protein (MBP), even in Th1 shifting environment, which consequently would lead to therapeutic effect in the MS diseased organ.
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PMID:Oral treatment of mice with copolymer 1 (glatiramer acetate) results in the accumulation of specific Th2 cells in the central nervous system. 1202 Sep 57

Glatiramer acetate (GA) is a mixture of synthetic polypeptides composed of four aminoacids. GA is very effective in suppression of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Various mechanisms of action of GA have been proposed, but the most important is probably the induction of antigen-specific suppressor T cells. Class one clinical trials have demonstrated that GA reduces the relapse rate and the accumulation of disability in relapsing-remitting (RR) MS. The positive effects on disease activity and disease progression are explained by the reduction of the number and volume of the active lesions as showed by Magnetic resonance imaging (MRI) studies. Moreover new MRI techniques suggest that GA may also have some neuroprotective effects. The drug is usually well tolerated with modest side effects. In vitro and in vivo animal studies have shown that GA is devoid of teratogenic or mutagenic effects. GA is a good alternative to interferon beta for treatment of RR-MS.
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PMID:Glatiramer acetate. 1203 Dec 14

Glatiramer acetate (GA, Copaxone), a standardized mixture of synthetic polypeptides, has now been approved also in Germany for the treatment of relapsing-remitting multiple sclerosis (RR-MS). After it had been shown effective in suppression of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), it was evaluated in several clinical studies. In these studies, GA could alter the natural history of MS by both reducing the relapse rate and affecting disability. The clinical therapeutic effect of GA was consistent with the effect on magnetic resonance imaging-defined disease activity and burden in a recent multicenter study. As a daily standard dose, 20 mg of GA is injected subcutaneously. The induction of GA-reactive T-helper 2-like regulatory suppressor cells is thought to be the main mechanism of action. The most common adverse effects are mild injection site reactions. A remarkable but rare adverse effect is the only transient immediate post-injection systemic reaction manifested by flushing, chest tightness, palpitations, and dyspnea. Antibodies to GA which are induced during GA treatment do not interfere with its clinical effects.
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PMID:[Treatment of multiple sclerosis with glatiramer acetate. Current aspects of mechanisms of action, pharmacokinetics, adverse effect profile and clinical studies]. 1204 Sep 79

Copolymer 1 (Cop 1, Copaxone [Teva Marion Partners, Kansas City, Missouri, USA]), a random amino acid copolymer of tyrosine (Y), glutamic acid (E), alanine (A), and lysine (K), reduces the frequency of relapses by 30% in relapsing-remitting multiple sclerosis (MS) patients. In the present study, novel random four-amino acid copolymers, whose design was based on the nature of the anchor residues of the immunodominant epitope of myelin basic protein (MBP) 85-99 and of the binding pockets of MS-associated HLA-DR2 (DRB1*1501), have been synthesized by solid-phase chemistry. Poly (Y, F, A, K) (YFAK) inhibited binding of the biotinylated MBP 86-100 epitope to HLA-DR2 molecules more efficiently than did either unlabeled MBP 85-99 or any other copolymer including Cop 1. Moreover, YFAK and poly (F, A, K) (FAK) were much more effective than Cop 1 in inhibition of MBP 85-99-specific HLA-DR2-restricted T cell clones. Most importantly, these novel copolymers suppressed experimental autoimmune encephalomyelitis, induced in the susceptible SJL/J (H-2(s)) strain of mice with the encephalitogenic epitope PLP 139-151, more efficiently than did Cop 1. Thus, random synthetic copolymers designed according to the binding motif of the human immunodominant epitope MBP 85-99 and the binding pockets of HLA-DR2 might be more beneficial than Cop 1 in treatment of MS.
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PMID:Novel synthetic amino acid copolymers that inhibit autoantigen-specific T cell responses and suppress experimental autoimmune encephalomyelitis. 1207 Mar 11

Glatiramer acetate (GA; copolymer-1, Copaxone) suppresses the induction of experimental autoimmune encephalomyelitis and reduces the relapse frequency in relapsing-remitting multiple sclerosis. Although it has become clear that GA induces protective degenerate Th2/IL-10 responses, its precise mode of action remains elusive. Because the cytokine profile of Th cells is often regulated by dendritic cells (DC), we studied the modulatory effects of GA on the T cell regulatory function of human DC. This study shows the novel selective inhibitory effect of GA on the production of DC-derived inflammatory mediators without affecting DC maturation or DC immunostimulatory potential. DC exposed to GA have an impaired capacity to secrete the major Th1 polarizing factor IL-12p70 in response to LPS and CD40 ligand triggering. DC exposed to GA induce effector IL-4-secreting Th2 cells and enhanced levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effect of GA is mediated via DC as GA does not affect the polarization patterns of naive Th cells activated in an APC-free system. Together, these results reveal that APC are essential for the GA-mediated shift in the Th cell profiles and indicate that DC are a prime target for the immunomodulatory effects of GA.
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PMID:Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. 1270 24

Glatiramer acetate (GA) (Copaxone(R)) is a worldwide-approved drug for the treatment of relapsing multiple sclerosis (MS), an autoimmune disease of the CNS. The drug is a synthetic copolymer with an amino acid composition based on the structure of myelin basic protein, one of the autoantigens implicated in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE). Developed initially as a "tool" to study EAE, the drug unexpectedly inhibited disease and was subsequently developed for the treatment of MS. The drug has been shown in controlled clinical trials to significantly reduce relapse rate and progression of disability in MS with long-term efficacy, remarkable safety, and tolerability. Efficacy as measured by magnetic resonance imaging parallels its clinical benefits as manifested by a reduction in gadolinium-enhancing lesions and brain atrophy. The mechanism of action of the drug in humans is believed to involve the induction of glatiramer-reactive regulatory cells, including CD4+ and CD8+ T-cells. Glatiramer-reactive Th2 cells are believed to enter the brain and, through cross-reactivity with myelin antigens, produce bystander suppression, antiinflammatory effects, and neuroprotection.
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PMID:Glatiramer acetate (Copaxone) therapy for multiple sclerosis. 1272 72

Glatiramer acetate (GA) is efficacious in reducing demyelinating-associated exacerbations in patients with relapsing-remitting multiple sclerosis (RRMS) and in several experimental autoimmune encephalomyelitis (EAE) models. Here we report that GA reduced the clinical and pathological signs of mice in chronic EAE induced by myelin oligodendrocyte glycoprotein (MOG). GA-treated mice demonstrated only mild focal inflammation, and less demyelination, compared with controls. Moreover, we also found minimal axonal disruption, as assessed by silver staining, antibodies against amyloid precursor protein (APP) and non-phosphorylated neurofilaments (SMI-32), in the GA-treated group. In conclusion, our study demonstrated for the first time that axonal damage is reduced following GA treatment in C57/bl mice with chronic MOG-induced EAE.
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PMID:Axonal damage is reduced following glatiramer acetate treatment in C57/bl mice with chronic-induced experimental autoimmune encephalomyelitis. 1451 44

The ability of a remedy to modulate the pathological process in the target organ is crucial for its therapeutic activity. Glatiramer acetate (GA, Copaxone, Copolymer 1), a drug approved for the treatment of multiple sclerosis, induces regulatory T helper 2/3 cells that penetrate the CNS. Here we investigated whether these GA-specific T cells can function as suppressor cells with therapeutic potential in the target organ by in situ expression of T helper 2/3 cytokines and neurotrophic factors. GA-specific cells and their in situ expression were detected on the level of whole-brain tissue by using a two-stage double-labeling system: (i) labeling of the GA-specific T cells, followed by their adoptive transfer, and (ii) detection of the secreted factors in the brain by immunohistological methods. GA-specific T cells in the CNS demonstrated intense expression of the brain-derived neurotrophic factor and of two antiinflammatory cytokines, IL-10 and transforming growth factor beta. No expression of the inflammatory cytokine IFN-gamma was observed. This pattern of expression was manifested in brains of normal and experimental autoimmune encephalomyelitis-induced mice to which GA-specific cells were adoptively transferred, but not in control mice. Furthermore, infiltration of GA-induced cells to the brain resulted in bystander expression of IL-10 and transforming growth factor beta by resident astrocytes and microglia. The ability of infiltrating GA-specific cells to express antiinflammatory cytokines and neurotrophic factor in the organ in which the pathological processes occur correlates directly with the therapeutic activity of GA in experimental autoimmune encephalomyelitis/multiple sclerosis.
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PMID:Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. 1461 35


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