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)

Vaccines are for healthy people, to prevent them from becoming ill. Such prophylactic vaccines have been a great success. Therapeutic vaccines become more and more important, especially as life expectancy increases. Efforts to develop vaccines against such diseases as cancer, AIDS, hepatitis, tuberculosis, Alzheimer disease, and mad cow disease have not yet reached the stage where they can be successfully used on a daily basis. However, significant progress has been made in the realm of autoimmune diseases, resulting (at least in one case) in an immunomodulatory vaccine against multiple sclerosis that was developed in the author's laboratory, and that is in daily use by about 100,000 patients. The drug or therapeutic vaccine against the exacerbating-remitting type of multiple sclerosis is a copolymer of four amino acid residues, denoted Copaxone, which are related to myelin basic protein. This paper discusses Copaxone as well as a candidate immunomodulatory vaccine against myasthenia gravis, a peptide derived from the nicotinic acetylcholine receptor. Copolymer 1 (Cop 1, glatiramer acetate, Copaxone) is a synthetic amino acid random copolymer that is immunologically cross-reactive with myelin basic protein and suppresses experimental allergic encephalomyelitis in several animal species. Cop 1 slows the progression of disability and reduces the relapse rate in exacerbating-remitting multiple sclerosis patients. Cop 1 is a potent inducer of T helper 2 (Th2) regulatory cells in mice and humans; and Th2 cells are found in both the brains and spinal cords of Cop 1-treated mice and humans. MG and experimental autoimmune MG are T cell-regulated, antibody-mediated autoimmune diseases. Two peptides, representing sequences of the human AChR-alpha-subunit, p195-212 and p259-271, are immunodominant T-cell epitopes in MG patients and two strains of mice. Altered peptide ligand, composed of the randomly arranged two single amino acid analogs inhibits in vitro and in vivo MG-associated autoimmune responses. The active suppression is mediated by the CD4+ CD25+ immunoregulatory cells and is associated with the downregulation of Th1-type cytokines and upregulation of the secretion of IL-10 and the immunosuppressive cytokine transforming growth factor beta.
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PMID:Immunomodulatory vaccines against autoimmune diseases. 1660 9

Axonal destruction and neuronal loss occur early during multiple sclerosis (MS), an autoimmune inflammatory central nervous system disease that frequently manifests with acute optic neuritis. Glatiramer acetate (GA) and interferon-beta-1b (IFN-beta-1b) are two immunomodulatory agents that have been shown to decrease the frequency of MS relapses. However, the question of whether these substances can slow neurodegeneration in MS patients is the subject of controversy. In a rat model of experimental autoimmune encephalomyelitis, we investigated the effects of GA and IFN-beta-1b on the survival of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. For each substance, therapy was started 14 days before immunization, on the day of immunization, or on the day of clinical disease onset. After myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis became clinically manifest, optic neuritis was monitored by recording visual evoked potentials. The function of RGCs was measured by electroretinograms. Although early GA or IFN-beta-1b treatment showed benefit on disease activity, only treatment with GA exerted protective effects on RGCs, as revealed by measuring neurodegeneration and neuronal function. Furthermore, we demonstrate that this GA-induced neuroprotection does not exclusively depend on the reduction of inflammatory infiltrates within the optic nerve.
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PMID:Effects of glatiramer acetate and interferon-beta on neurodegeneration in a model of multiple sclerosis: a comparative study. 1700 91

Glatiramer acetate (GA), formerly known as copolymer 1, is a mixture of synthetic polypeptides composed of four amino acids resembling the myelin basic protein (MSP). GA has been shown to be highly effective in preventing and suppressing experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Therefore, it was tested in several clinical studies and so approved for the immunomodulatory treatment of relapsing-type MS. In contrast to other immunomodulatory MS therapies, GA has a distinct mechanism of action: GA demonstrates an initial strong promiscuous binding to major histocompatibility complex molecules and consequent competition with various (myelin) antigens for their presentation to T cells. In addition, antigen-based therapy generating a GA-specific immune response seems to be the prerequisite for GA therapy. GA treatment induces an in vivo change of the frequency, cytokine secretion pattern and the effector function of GA-specific CD4+ and CD8+ T cells, probably by affecting the properties of antigen-presenting cells such as monocytes and dendritic cells. As demonstrated extensively in animal experiments, GA-specific, mostly, T helper 2 cells migrate to the brain and lead to in situ bystander suppression of the inflammatory process in the brain. Furthermore, GA-specific cells in the brain express neurotrophic factors like the brain-derived neurotrophic factor (BDNF) in addition to anti-inflammatory T helper 2-like cytokines. This might help tip the balance in favor of more beneficial influences because there is a complex interplay between detrimental and beneficial factors and mediators in the inflammatory milieu of MS lesions.
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PMID:Glatiramer acetate: mechanisms of action in multiple sclerosis. 1753 58

Glatiramer acetate (GA) is a mixture of synthetic polypeptides composed of four amino acids resembling myelin basic protein (MBP). GA has been shown to be effective in preventing and suppressing experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. It was tested in several clinical studies and approved for the immunomodulatory treatment of relapsing-type MS in 1996. Glatiramer acetate demonstrates a strong promiscuous binding to major histocompatibility complex molecules and inhibits the T cell response to several myelin antigens. In addition, it was shown to act as a T cell receptor antagonist for the 82-100 MBP epitope. Glatiramer acetate treatment causes in vivo changes of the frequency, cytokine secretion pattern and effector function of GA-specific T cells. It was shown to induce GA-specific regulatory CD4(+) and CD8(+) T cells and a TH1-TH2 shift with consecutively increased secretion of antiinflammatory cytokines. GA-specific TH2 cells are able to migrate across the blood-brain barrier and cause in situ bystander suppression of autoaggressive TH1 T cells. In addition glatiramer acetate was demonstrated to influence antigen presenting cells (APC) such as monocytes and dendritic cells. Furthermore secretion of neurotrophic factors with potential neuroprotective effects was shown.
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PMID:Glatiramer acetate: mechanisms of action in multiple sclerosis. 1764 35

Treatment with glatiramer acetate (GA, copolymer-1, Copaxone), a drug approved for multiple sclerosis (MS), in a mouse model promoted development of anti-inflammatory type II monocytes, characterized by increased secretion of interleukin (IL)-10 and transforming growth factor (TGF)-beta, and decreased production of IL-12 and tumor necrosis factor (TNF). This anti-inflammatory cytokine shift was associated with reduced STAT-1 signaling. Type II monocytes directed differentiation of T(H)2 cells and CD4+CD25+FoxP3+ regulatory T cells (T(reg)) independent of antigen specificity. Type II monocyte-induced regulatory T cells specific for a foreign antigen ameliorated experimental autoimmune encephalomyelitis (EAE), indicating that neither GA specificity nor recognition of self-antigen was required for their therapeutic effect. Adoptive transfer of type II monocytes reversed EAE, suppressed T(H)17 cell development and promoted both T(H)2 differentiation and expansion of T(reg) cells in recipient mice. This demonstration of adoptive immunotherapy by type II monocytes identifies a central role for these cells in T cell immune modulation of autoimmunity.
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PMID:Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. 1767 50

The interplay between demyelination and remyelination is critical in the progress of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). In the present study, we explored the capacity of glatiramer acetate (GA, Copaxone) to affect the demyelination process and/or lead to remyelination in mice inflicted by chronic EAE, using both scanning electron microscopy and immunohistological methods. Spinal cords of untreated EAE mice revealed substantial demyelination accompanied by tissue destruction and axonal loss. In contrast, in spinal cords of GA-treated mice, in which treatment started concomitantly with disease induction (prevention), no pathology was observed. Moreover, when treatment was initiated after the appearance of clinical symptoms (suppression) or even in the chronic disease phase (delayed suppression) when substantial demyelination was already manifested, it resulted in a significant decrease in the pathological damage. Detection of oligodendrocyte progenitor cells (OPCs) expressing the NG2 or O4 markers via colocalization with the proliferation marker BrdU indicated their elevated levels in spinal cords of GA-treated mice. The mode of action of GA in this system is attributed to increased proliferation, differentiation, and survival of OPCs along the oligodendroglial maturation cascade and their recruitment into injury sites, thus enhancing repair processes in situ.
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PMID:Demyelination arrest and remyelination induced by glatiramer acetate treatment of experimental autoimmune encephalomyelitis. 1867 87

Glatiramer acetate (GA, copolymer-1, Copaxone), a therapy approved for treatment of multiple sclerosis (MS), prevents and reverses experimental autoimmune encephalomyelitis, the animal model of MS. In central nervous system autoimmune disease, GA is thought to act through modulation of antigen-presenting cells, such as monocytes, mediating an antigen-independent T(h)2 shift and development of FoxP3+ regulatory T cells. Recent reports indicate that GA may also be effective in models of other autoimmune diseases such as uveoretinitis, inflammatory bowel disease and graft rejection. To date, the potential effect of GA in lupus animal models has not been described. (NZB x BXSB)F1, male mice bearing Y-linked autoimmune acceleration , is a lupus-prone mouse model which is associated with a monocytosis accelerating disease progression. These mice were treated with GA before disease onset until death and both mortality rate and biological parameters were assessed to investigate whether GA may be beneficial in this spontaneous model of systemic lupus erythematosus. GA exerted no beneficial effect on the median survival after up to 7 months of treatment. Humoral and cellular parameters used as markers for lupus progression, such as anti-chromatin, anti-double-stranded DNA and anti-erythrocytes antibodies, hematocrit and monocytosis, were similarly unchanged. Our study demonstrates that GA has no significant effect on the progression of the (NZB x BXSB)F1 lupus-prone animal model. These results reinforce the hypothesis that GA may exert its beneficial effect in some specific autoimmune diseases only.
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PMID:Glatiramer acetate treatment does not modify the clinical course of (NZB x BXSB)F1 lupus murine model. 1868 87

We analyzed the medical records and cerebral imaging of 30 children with early onset multiple sclerosis to compare the clinical and neuro-radiological features with acute demyelinating encephalomyelitis and adult multiple sclerosis. The female:male ratio was 1.3 before the age of 12 years and increased to 4.3 after age 12 years. Optic neuritis and pyramidal dysfunction were the most common presenting clinical features. The most common radiological features at first imaging were periventricular (77.2%), corpus callosal demyelination (63.6%), gadolinium enhancement (62.5%), and Dawson's fingers (40.9%). The median relapse rate per patient year was 1.2 ([IQR] 0.6-2.0). Seven patients reached a moderate Expanded-Disability-Status-Scale score of 3 and 3 patients were more severely affected (score of 6). Expanded-Disability-Status-Scale score increased by 0.7 for every relapse. Ten patients were commenced on immunomodulatory therapy (Interferon beta 1a, n = 9; Interferon beta 1b, n = 3; or Glatiramer acetate, n = 1), the majority of who had minimal side effects and a reduction in relapse rate.
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PMID:Multiple sclerosis in childhood: clinical and radiological features. 1894 Sep 15

Avulsion of ventral roots induces degeneration of most axotomized motoneurons. At present there are no effective strategies to prevent such neuronal loss and to preserve the affected spinal circuits. Interestingly, changes in the spinal cord network also occur during the course of the experimental model of multiple sclerosis (experimental autoimmune encephalomyelitis-EAE). Glatiramer acetate (GA) significantly reduces the seriousness of the symptoms during the exacerbation of EAE. However, little is known about its effects on motoneurons. In the present study, we investigated whether GA has an influence on synapse plasticity and glial reaction after ventral root avulsion (VRA). Lewis rats were subjected to the avulsion of lumbar ventral roots and treated with GA. The animals were sacrificed after 14 days of treatment and the spinal cords processed for immunohistochemistry. A correlation between the synaptic changes and glial activation was obtained by performing immunolabeling against synaptophysin, GFAP and Iba-1. GA treatment preserved synaptophysin labeling, and significantly reduced the glial reaction in the area surrounding the axotomized motoneurons. After ventral root avulsion, GA treatment was also neuroprotective. The present results indicate that the immunomodulator GA has an influence on the stability of nerve terminals in the spinal cord, which may in turn contribute to future treatment strategies after proximal lesions to spinal motoneurons.
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PMID:Glatiramer acetate positively influences spinal motoneuron survival and synaptic plasticity after ventral root avulsion. 1910 52

Glatiramer acetate (GA or Copaxone) is a drug used to treat experimental autoimmune encephalomyelitis in mice and multiple sclerosis in human. Here, we describe a new mechanism of action for this drug. GA enhanced the cytolysis of human NK cells against autologous and allogeneic immature and mature monocyte-derived dendritic cells (DCs). This drug reduced the percentages of mature DCs expressing CD80, CD83, HLA-DR or HLA-I. In contrast, it did not modulate the percentages of NK cells expressing NKG2D, NKp30, or NKp44. Nonetheless, anti-NKp30 or anti-CD86 inhibited GA-enhanced human NK cell lysis of immature DCs. Hence, CD86, and NKp30 are important for NK cell lysis of immature DCs, whereas CD80, CD83, HLA-DR and HLA-I are important for the lysis of mature DCs when GA is used as a stimulus. Further, GA inhibited the release of IFN-gamma 24 h but increased the release of TNF-alpha 48 h after incubation with NK cells.
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PMID:Modulation of natural killer cell cytotoxicity and cytokine release by the drug glatiramer acetate. 1927 66


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