Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Neurotropic strains of mouse hepatitis virus (MHV) have been used extensively for the study of viral pathogenesis in the central nervous system (CNS), serving as models for human neurological diseases such as multiple sclerosis (MS). MHV strains A59 and JHMV both cause acute and chronic encephalomyelitis and demyelination in susceptible strains of mice and rats. In acute disease, CNS damage is most likely the result of lytic infection in neurons and oligodendrocytes, and death can be prevented by the adoptive transfer of Class I-restricted CD8+ T cells. However, in later stages of the disease induced by some MHV strains, virus tends to be restricted to astrocytes in a nonlytic infection, and the immune response appears to contribute to CNS damage. These data lead us to suggest that the astrocyte may play a central role in the neuropathogenesis of MHV infection. Consistent with this possibility, A59 has been reported to induce the expression of Class I molecules of the major histocompatibility complex (MHC) in glial cells following infection in vivo and in vitro. In this communication, we have examined the influence of persistent infection by both A59 and JHMV on MHC Class I expression in primary murine astrocytes. Persistence was characterized by the presence of intracellular viral antigen and mRNA in the absence of detectable infectious virus particles. Under these conditions, JHMV, but not A59, inhibited constitutive expression of the H-2 Kb molecule, with the magnitude of inhibition increasing with postinfection time. A59 was not able to induce Class I during persistence, presumably due to the lack of infectious virus particles. Class I expression was restored by the addition of gamma-interferon (IFN-gamma) to astrocytes persistently infected with either A59 or JHMV. Thus, Class I inhibition is not a permanent consequence of JHMV persistence, and persistence does not interfere with normal signalling pathways for Class I induction.
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PMID:Effect of persistent mouse hepatitis virus infection on MHC class I expression in murine astrocytes. 771 17

A chronic relapsing-remitting form of experimental autoimmune encephalomyelitis was induced in the common marmoset Callithrix jacchus following a single immunization with human white matter. Individual animals in this species are born as natural bone marrow chimeras, allowing transfer of functional T-cell populations between genetically distinct siblings. The acute disease was characterized clinically by mild neurological signs. Pathologically, the disease was characterized by perivascular mononuclear cell infiltrates, large foci of primary demyelination, and reactive astrogliosis. No animal displayed hemorrhagic-necrotic lesions or polymorphonuclear cell infiltrates characteristic of other acute forms of primate experimental autoimmune encephalomyelitis. A late spontaneous relapse occurred in each of 2 animals followed for 3 to 12 months subsequent to recovery from the acute attack. In these animals, chronic lesions consisted of mononuclear cell infiltrates within large sharply defined areas of demyelination and astrogliosis, and resembled active plaques of chronic multiple sclerosis. Proliferative responses to myelin basic protein but not to myelin proteolipid protein were present in peripheral blood lymphocytes of immunized animals. Furthermore, myelin basic protein-reactive T-cell lines derived from immunized donors induced clinical signs of experimental autoimmune encephalomyelitis when adoptively transferred into a sibling, indicating that myelin basic protein-reactive T cells can induce disease in this species. Because of its clinical and pathological similarity to human multiple sclerosis and the ability to adoptively transfer experimental autoimmune encephalomyelitis, this model system should prove useful in the analysis of the immunological mechanisms responsible for autoimmune demyelination in outbred primates.
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PMID:Active and passively induced experimental autoimmune encephalomyelitis in common marmosets: a new model for multiple sclerosis. 771 89

The Daniels strain of Theiler's virus causes a persistent infection of the white matter of spinal cord of susceptible mice, with chronic inflammation and primary demyelination. Inbred 129Sv mice are resistant to this infection; they present with mild encephalomyelitis and clear the infection within a matter of days. A very different outcome was observed with inbred 129Sv mice whose receptors for interferon alpha/beta or interferon gamma had been inactivated by homologous recombination. The former presented severe encephalomyelitis with acute infection of neurons, particularly in brain and hippocampus, and extensive infection with necrosis of the choroid plexus. Most animals died of this acute disease. The latter, presented the same early encephalomyelitis as the control 129Sv mice. However, they remained persistently infected and developed a very severe late infection of the white matter with extensive primary demyelination. This late disease looked like an exacerbated form of the chronic demyelinating disease observed in susceptible inbred mice such as the SJL/J or FVB strains. Our results show that the two interferon systems play nonredundant roles in the resistance of the 129Sv mouse to the infection by Theiler's virus. They also lend support to the notion that the Ifg gene is involved in the resistance/susceptibility of inbred strains of mice to persistent infection by this picornavirus.
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PMID:Theiler's virus infection of 129Sv mice that lack the interferon alpha/beta or interferon gamma receptors. 775 99

Vaccinia-virus (VV) recombinants encoding either the nucleocapsid (N) or the spike (S) protein of MHV-JHM were constructed to study the role of the immune response against defined coronavirus antigens. For the S-protein, a fusogenic (Sfus+) or non fusogenic variant (Sfus-) of the gene was inserted into the VV genome. A strong protection against acute encephalomyelitis (AE) was mediated in Lewis rats which were immunized by VV-Sfus+ and challenged with an otherwise lethal dose of MHV-JHM before the induction of S-specific IgG antibodies. By contrast, a VV recombinant encoding a variant non fusogenic S-protein or the N-protein was not capable conferring protection. In addition, we demonstrated that MHV-JHM S-specific IgG antibodies elicited before MHV-JHM challenge modulated the disease process, changing it from an acute disease to subacute demyelinating encephalomyelitis (SDE).
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PMID:Recombinant vaccinia viruses which express MHV-JHM proteins: protective immune response and the influence of vaccination on coronavirus-induced encephalomyelitis. 820 61

Tumor necrosis factor alpha (TNFalpha) activity was measured in serum and cerebrospinal fluid (CSF) of Lewis rats after experimental allergic encephalomyelitis (EAE) induction and during the clinical course of acute disease. TNFalpha bioactivity expression preceded the clinical symptoms and paralleled the severity of disease. We further investigated the identity of the central nervous system (CNS) cells involved in TNFalpha expression and their regional localization during EAE. Tissue sections of brain, cerebellum, dorsal spinal cord and optic nerve were studied by indirect double labelling immunofluorescence. Spinal cord white matter and optic nerve showed a widespread TNFalpha immunoreactivity at critical stages of EAE in macrophages/microglia and astrocytes. We have shown changes in CSF/serum albumin ratio and immunoglobulin G index during EAE. Our results confirm the very important role of TNFalpha in EAE.
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PMID:Myelin-induced experimental allergic encephalomyelitis in Lewis rats: tumor necrosis factor alpha levels in serum and cerebrospinal fluid immunohistochemical expression in glial cells and macrophages of optic nerve and spinal cord. 859 90

Previous studies have detected gamma delta T cells in multiple sclerosis and experimental allergic encephalomyelitis (EAE) lesions but their role remains obscure. In the present study, we assessed gamma delta T cell dynamics and distribution in spleen and central nervous system (CNS) from mice with relapsing-remitting EAE, and studied the effect of depleting these cells on clinical and pathologic expression of disease using the mAb GL3. By immunohistochemistry and FACS analysis, striking disease-related changes were observed in the gamma delta T cell population in the CNS. FACS analysis showed that while gamma delta T cells remained low in the spleen (approximately 2% total CD3+ T cells) at all stages, in the CNS they increased to approximately 12% at the height of the acute attack, fell to approximately 5% during the recovery phase, but rose again to approximately 12% during the chronic phase. In animals in which gamma delta T cells were depleted immediately before the onset of acute disease, or during the chronic stage, a striking and significant reduction in the severity of the clinical signs was observed that was associated with a decrease in the percentage of CD3+/gamma delta T cells in the CNS. In depleted animals a statistically significant reduction in inflammation and demyelination was noted during the acute stage, but only marginal effects on these disease parameters were found in the chronic phase. Taken together, the data support the conclusion that gamma delta T cells play an important role in the pathogenesis of EAE in mice during both acute and chronic/progressive phases of the disease process.
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PMID:A pathogenic role for gamma delta T cells in relapsing-remitting experimental allergic encephalomyelitis in the SJL mouse. 875 49

Chemokines are a family of small-molecular-weight cytokines that induce chemotaxis and chemokinesis of leukocytes. These molecules are ligands for seven-transmembrane, G-protein-linked receptors and are known to activate integrins on the surface of leukocytes and other cells as well as induce a number of signaling events. They play a significant role in the migration of leukocytes from blood into tissue during inflammatory processes. We tested the role of chemokines in experimental autoimmune encephalomyelitis (EAE) and found that macrophage inflammatory protein-1alpha (MIP-1alpha) correlated with acute disease development, whereas monocyte chemotactic protein-1 (MCP-1) did not. In contrast, MCP-1 production in the central nervous system correlated with relapsing EAE development. Moreover, anti-MIP-1alpha, but not anti-MCP-1, inhibited development of acute but not relapsing EAE, whereas anti-MCP-1 significantly reduced the severity of relapsing EAE. To test the effects of chemokines on the differentiation of naive T cells, TCR transgenic splenic T cells (Tg+ T cells) from DO11.10 OVA TCR transgenic mice were used as a source of Th0 cells and were stimulated with specific anti-clonotypic monoclonal antibodies in the presence of MIP-1alpha, MCP-1, or controls. MIP-1alpha drove Th0 cells to differentiate to Th1, whereas MCP-1 drove Th0 cells to differentiate to Th2. Similarly, MCP-1, but not MIP-1alpha significantly inhibited the adoptive transfer of EAE when included in in vitro activation cultures, further suggesting a regulatory anti-inflammatory property. These results suggest a differential role for CC chemokines in the development and activation of T cells during autoimmune inflammatory diseases.
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PMID:MIP-1alpha and MCP-1 differentially regulate acute and relapsing autoimmune encephalomyelitis as well as Th1/Th2 lymphocyte differentiation. 936 24

The progression of experimental allergic encephalomyelitis (EAE) in certain mouse strains has been reported to involve a broadening of the response to myelin antigens, apparently resulting from priming to endogenous determinants of the myelin sheath. The phenomenon has been termed determinant spread. Interest in this effect has centered on the mechanism it offers to explain the progressive, relapsing and remitting course of EAE and indeed of multiple sclerosis. We have conducted a systematic, longitudinal study in SJL mice to look for determinant spread during relapsing and remitting EAE, correlating epitope recognition and cytokine production with disease severity. Disease was induced using three of the four encephalitogenic proteolipid protein or myelin basic protein epitopes, and responses to each of four epitopes recognized by SJL T cells were tracked through acute disease, remission and relapse. The responses of lymph node cells, splenocytes and central nervous system (CNS)-infiltrating T cells were analyzed. While marginal, transient responses to secondary epitopes were detectable in splenocytes, CNS-infiltrating cells showed a dominant response to the original disease-inducing epitope without evidence of a shift to other determinants during relapse. Disease relapse was correlated with an increase in CNS-infiltrating cells and a high proliferative and interferon (IFN)-gamma response to the disease-inducing peptide. During remission, there was a decrease in numbers of cells infiltrating the CNS. These cells were down-regulated, showing low if any response to the myelin peptides tested as measured by proliferation, production of IFN-gamma or production of IL-4. Our findings argue strongly against a causal role for determinant spread in disease relapse as observed in these models of EAE.
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PMID:Relapsing and remitting experimental allergic encephalomyelitis: a focused response to the encephalitogenic peptide rather than epitope spread. 939 20

Relapsing experimental autoimmune encephalomyelitis (R-EAE) is an immune-mediated demyelinating central nervous system (CNS) disease. Myeloablation and syngeneic bone marrow transplantation (SBMT), when performed at the peak of acute disease (day 14), prevented glial scarring and ameliorated the disease severity. In contrast, when syngeneic BMT was performed late in chronic phase (day 78), significant glial scarring remained and the clinical severity did not differ significantly from that of the controls. After SBMT in either the acute or chronic phase of disease, the posttransplant immune system remained responsive to myelin epitopes as determined by in vitro proliferation and interferon-gamma (IFN-gamma) production. However, in mice undergoing SBMT, in vivo delayed-type hypersensitivity (DTH) responses were significantly decreased while IFN-gamma RNA levels and inflammatory infiltrates within the CNS were slightly improved. We conclude that failure of SBMT to improve the clinical disease when performed in chronic phase may be due to preexisting glial scarring. We also conclude that in the absence of glial scarring and irreversible neuronal injury, in vivo DTH responses and histology are better predictors of clinical improvement than in vitro proliferation or IFN-gamma cytokine production.
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PMID:Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation for relapsing experimental autoimmune encephalomyelitis. 951 63

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are characterized by episodic neurologic dysfunction, perivascular mononuclear cell inflammation occurring mainly in white matter, and demyelination. Strong circumstantial evidence supports the conclusion that macrophage activation and local production of proinflammatory cytokines are necessary for disease induction and lesion formation. We now report that CNI-1493, a small m.w. compound, which inhibits macrophage activation and subsequent proinflammatory cytokine production, suppresses EAE induced in the genetically susceptible SJL/J mouse. Treatment with 5 mg/kg/day completely suppressed mild disease (clinical index of 1.6 +/- 0.5 in the untreated group as compared with 0.0 +/- 0.0 for the treated group) and significantly reduced acute disease (clinical index of 4.3 +/- 0.7 in the untreated group as compared with 0.5 +/- 0.3 for the treated group). Suppression of clinical manifestations of the disease correlated with a significant decrease in histopathology and proinflammatory cytokine expression at the lesion site. Moreover, drug treatment during the chronic phase resulted in amelioration of clinical signs. The data presented here should prove useful in developing novel chemotherapeutic approaches for the treatment of MS.
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PMID:Prevention and treatment of experimental autoimmune encephalomyelitis by CNI-1493, a macrophage-deactivating agent. 960 64


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