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)

A major question in neurobiology is whether myelin repair can restore neurological function following the course of a severe, progressive CNS demyelinating disease that induces axonal loss. In this study we used Theiler's murine encephalomyelitis virus (TMEV) to induce a chronic progressive CNS demyelinating disease in mice that was immune-mediated and pathologically similar to human multiple sclerosis. Because immunosuppression of chronically TMEV-infected mice has been shown to enhance myelin repair, we first addressed the potential roles of CD4(+) and CD8(+) T cells in the inhibition of CNS remyelination during chronic disease. TMEV infection of susceptible PL/J mice deficient in CD4(+) but not CD8(+) T cells demonstrated a significant increase in severity of pathogenesis when compared with wild-type controls. This was characterized by enhanced demyelination, spinal cord atrophy, neurological deficits, and mortality. Interestingly, the PL/J CD4(-/-) mice that survived to the chronic stage of the disease had nearly complete spontaneous myelin repair mediated by both oligodendrocytes and infiltrating Schwann cells. Therefore, we next addressed whether this spontaneous myelin repair was associated with improved neurological function despite the increased pathology. Of interest, all surviving PL/J CD4(-/-) mice showed partial restoration of motor coordination and gait that coincided temporally with spontaneous myelin repair. Furthermore, functional recovery of motor coordination correlated strongly with the percentage of myelin repair mediated by Schwann cells, whereas restoration of hindlimb gait correlated with oligodendrocyte-mediated myelin repair. This is the first study to demonstrate that spontaneous remyelination correlates with partial restoration of neurological function during the course of a progressive, immune-mediated CNS demyelinating disease. Of greater importance, functional recovery occurred despite previous severe demyelination and spinal cord atrophy.
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PMID:Spontaneous remyelination following extensive demyelination is associated with improved neurological function in a viral model of multiple sclerosis. 1140 35

Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a multiple sclerosis (MS) model, is a central nervous system (CNS) demyelinating disease characterized by early peripheral T cell responses to virus epitopes which spreads to myelin epitopes during chronic disease. We show that CD4(+) T cells isolated from the spinal cords of chronically infected SJL mice proliferate and secrete pro-inflammatory cytokines upon in vitro challenge with both TMEV epitopes and proteolipid protein (PLP(139-151)). Importantly, myelin-specific tolerance induced by intravenous administration of MP4, a fusion of the myelin proteins myelin basic protein (MBP) and PLP, to SJL mice with ongoing TMEV-IDD attenuated disease progression and resulted in significantly less demyelination and decreased inflammatory cell infiltration in the CNS. Paradoxically, peptide-specific splenic T cell proliferative and IFN-gamma responses were enhanced in the tolerized mice. Collectively, these results indicate that myelin-specific T cell responses contribute to chronic disease progression in this virus-induced model of MS, and suggest caution in the use of antigen-specific tolerance for treatment of ongoing autoimmune disease.
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PMID:Myelin-specific tolerance attenuates the progression of a virus-induced demyelinating disease: implications for the treatment of MS. 1188 Jan 45

Microarray analysis of multiple sclerosis (MS) lesions obtained at autopsy revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 and -17, interferon-gamma and associated downstream pathways. Comparison of two poles of MS pathology--acute lesions with inflammation versus 'silent' lesions without inflammation--revealed differentially transcribed genes. Some products of these genes were chosen as targets for therapy of experimental autoimmune encephalomyelitis (EAE) in mice. Granulocyte colony-stimulating factor is upregulated in acute, but not in chronic, MS lesions, and the effect on ameliorating EAE is more pronounced in the acute phase, in contrast to knocking out the immunoglobulin Fc receptor common gamma chain where the effect is greatest on chronic disease. These results in EAE corroborate the microarray studies on MS lesions. Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy.
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PMID:Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. 1198 84

The development of clinical symptoms in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) involves T-cell activation and migration into the central nervous system, production of glial-derived inflammatory molecules, and demyelination and axonal damage. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPARgamma ligand pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein. Pioglitazone also reduced clinical signs when it was provided after disease onset. Clinical symptoms were reduced by two other PPARgamma agonists, suggesting a role for PPARgamma activation in protective effects. The suppression of clinical signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen-dependent interferon-gamma production from EAE-derived T cells. These results suggest that orally administered PPARgamma agonists could provide therapeutic benefit in demyelinating disease.
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PMID:Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis. 1211 74

Theiler's murine encephalomyelitis virus (TMEV) disease is induced following intracerebral inoculation of TMEV, a member of picornavirus family, in susceptible animals. The pathogenesis of paralytic syndrome is associated with a chronic progressive demyelinating disease characterized by perivascular of immune inflammatory cells. Although TMEV induced demyelinating disease (TMEV IDD) is initiated by virus specific CD4+ T cells targeting CNS persistent virus, CD4+ T cell responses against self myelin epitopes activated via epitope spreading contribute to chronic disease pathogenesis. In the present report we delineated possible pathogenic mechanisms related with inflammatory process, leading to demyelination and axonal loss. The importance of proinflammatory cytokines in sustaining the inflammatory process and cause direct oligodendrotoxicity is emphasized. Different approaches in therapeutic strategies affecting cytokines are also presented.
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PMID:[Theiler's virus encephalomyelitis infection as a model for multiple sclerosis: cytokines and pathogenic mechanisms]. 1243 2

The integrin VLA-4 has been shown to play a key role in the entry of antigen-specific T cells into the CNS during autoimmune demyelination. Treatment of animals with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, with antibodies to VLA-4 is known to suppress acute disease. In the present study, a synthetic antagonist of VLA-4 (TBC 3486) was injected subcutaneously into mice adoptively sensitized for chronic relapsing EAE. TBC 3486 was administered daily for 14 days at early (before acute signs) and late time points (during chronic disease). Early treatment led to marked delay in disease onset and reduction in clinical severity and demyelination. After termination of treatment, clinical severity remained lower than in controls for more than 1 week. TBC 3486-treated animals showing no clinical signs (at the height of disease in controls) displayed moderate levels of inflammation but little damage to myelin. Late administration of TBC 3486 to animals with chronic EAE had no effect clinically. Immunocytochemistry and Western blotting of CNS tissue from acutely treated animals supported a moderate shift toward a Th2-type cytokine profile after treatment. Thus, TBC 3486 effectively delayed and reduced the acute (but not chronic) phase of EAE, and this amelioration correlated with changes in the inflammatory molecule profile.
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PMID:Differential efficacy of a synthetic antagonist of VLA-4 during the course of chronic relapsing experimental autoimmune encephalomyelitis. 1252 29

Treosulfan (dihydroxybusulfane, DHB, L-threitol-1,4-bis [methane sulfonate]) is a cytostatic alkylating agent with a favorable profile of side effects. Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) induced in DA (RT1(av1)) rats resembles multiple sclerosis (MS) in many aspects since central nervous system (CNS) pathology shows inflammation, demyelination and axonal loss. Moreover, DA rats develop a chronic disease course. We here explored the efficacy of treosulfan in the treatment of MOG-induced EAE in DA rats. A single dose of treosulfan (1 g/kg body weight i.p.) at the day of immunization significantly reduced disease severity compared with PBS-treated controls. In addition, after disease had evolved, a single dose of treosulfan (1 g/kg body weight) given i.p. on day 14 post-immunization (p.i.) improved long-term disease outcome. Treatment with treosulfan resulted in reduced mRNA expression of IL-12 and interferon (IFN)-gamma in draining lymph nodes and reduced numbers of IFN-gamma-secreting MOG-specific T cells. No myelosuppression was observed. Treosulfan was applied to different subsets of cultured human blood mononuclear cells in order to asses the effects on human immune cells in vitro: Treosulfan reduced proliferative capacity and increased apoptosis in T cells and antigen-presenting cells. In light of the beneficial effects in EAE in vivo and the in vitro immunosuppressive and pro-apoptotic capacities in cultured human mononuclear immune effector cells, these data may support a potential role of treosulfan, an agent with high immunosuppressive capacity and low toxicity, in the treatment of MS.
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PMID:Action of treosulfan in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis and human lymphocytes. 1459 95

Acute immunosuppression with lymphocytic agents given at maximally tolerated doses, followed by hematopoietic stem cell rescue achieved by autologous bone marrow or peripheral blood stem cell transplantation (BMT), has proved effective in various experimental models of autoimmunity. The rationale for such an approach in autoimmune diseases is based on the concept of lymphoablation of self-reactive lymphocytes followed by de novo immune system reconstitution, which, in the presence of the autoantigens in the thymus, may reinduce self-tolerance. Our previous work shows that in experimental autoimmune encephalomyelitis (EAE), autologous/syngeneic BMT not only prevents the appearance of paralytic signs, but can also partially reverse chronic disease and induce long-term, antigen-specific tolerance. However, there are serious reservations to be considered when interpreting these data and before applying similar protocols in patients with multiple sclerosis. (1) The model of EAE is not a completely reliable model of multiple sclerosis. (2) In animals with chronic EAE, although further relapses were prevented, the established paralysis was usually not reversible. According to recent data, in chronic multiple sclerosis (MS) lesions, damage caused by axonal loss/transection and cortical/spinal cord atrophy is irreversible and probably amenable to immunotherapy. (3) Long-term, antigen-specific tolerance may be induced with BMT, but not in all cases; in passively induced CR-EAE, many of the mice relapsed upon challenge with myelin antigens, which may indicate that the presence of the immunizing, myelin antigens (on the site of immunization) during the process of immune reconstitution is critical for induction of tolerance. Finally, one should weigh the procedure-related risks (including mortality of up to 5%) of bone marrow or peripheral stem cell transplantation (SCT). A more radical solution for autoimmunity may involve the use of non-myeloablative allogeneic transplantation.
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PMID:Hematopoietic stem cell transplantation in multiple sclerosis: experimental evidence to rethink the procedures. 1526 62

Interferon-gamma has been shown to be important for the resolution of inflammation associated with CNS autoimmunity. Because one of the roles of gamma delta T cells is the regulation of inflammation, we asked whether gamma delta T cells were able to regulate CNS inflammation using the autoimmune disease mouse model experimental autoimmune encephalomyelitis (EAE). We show that the presence of gamma delta T cells was needed to promote the production of IFN-gamma by both CD4 and CD8 T cells in the CNS before the onset of EAE. This regulation was shown to be independent of the ability of gamma delta T cells to produce IFN-gamma, and was specific to T cells in the CNS, as no alterations in IFN-gamma production were detectable in gamma delta T cell-deficient mice in the spleen and lymph nodes of mice with EAE or following immunization. Analysis of TCR gamma delta gene usage in the CNS showed that the only TCR delta V gene families present in the CNS before EAE onset are from the DV7s6 and DV105s1 gene families. We also show that the primary IFN-gamma-producing cells in the CNS are the encephalitogenic T cells, and that gamma delta T cell-deficient mice are unable to resolve EAE disease symptoms like control mice, thus exhibiting a long-term chronic disease course similar to that observed in IFN-gamma-deficient mice. These data suggest that CNS resident gamma delta T cells promote the production of IFN-gamma by encephalitogenic T cells in the CNS, which is ultimately required for the recovery from EAE.
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PMID:Gamma delta T cell regulation of IFN-gamma production by central nervous system-infiltrating encephalitogenic T cells: correlation with recovery from experimental autoimmune encephalomyelitis. 1526 86

Many individuals with multiple sclerosis (MS) experience clinically significant pain, yet the underlying neural mechanisms for MS pain are not understood. Experimental autoimmune encephalomyelitis (EAE) is a well-studied disease in rodents that mimics many clinical and pathological features of MS, including central nervous system inflammation and demyelination. To determine whether EAE is an appropriate model for MS-related pain, nociceptive responses in both male and female SJL mice were measured before and after immunization with myelin proteolipid protein peptide 139-151 (PLP(139-151)) in complete Freund's adjuvant to induce 'active' EAE. To determine if changes in nociception were due to direct effects of encephalitogenic T cells, nociceptive responses in female SJL mice were measured following the transfer of activated, PLP(139-151) specific T cells to induce 'passive' EAE. Both forepaw and tail withdrawal latencies to a radiant heat stimulus were measured. In both active and passive EAE, there was an initial increase in tail withdrawal latency (hypoalgesia) that peaked several days prior to the peak in motor deficits during the acute disease phase. During the chronic disease phase, tail withdrawal latencies decreased and were significantly faster than control latencies for up to 38 days post-immunization. This hyperalgesia was seen in both sexes and in both active and passive EAE models. Forepaw withdrawal latencies remained within 1-2 s of baseline latencies for the entire testing period, indicating that the hypoalgesia and hyperalgesia were most pronounced in clinically affected body regions. These results suggest that both active and passive EAE are useful models of MS-related pain.
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PMID:Hyperalgesia in an animal model of multiple sclerosis. 1528 96


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