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)

Pentoxifylline (PTX) has been recently shown to have a variety of immunomodulatory effects. PTX suppresses the production of tumor necrosis factor-alpha (TNF-alpha) and T helper type 1 (Th1) cytokine, interferon-gamma (IFN-gamma), whereas it increases the production of Th2 cytokines, such as interleukin-4 (IL-4) and IL-10. In the pathogenesis of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD), encephalitogenic Th1 cells may play a major role. We examined the effect of PTX treatment on TMEV-IDD. We treated SJL/J mice, inoculated TMEV intracerebrally, with either PTX or saline from days -2 to 12 and days 14 to 27 postintracerebral infection. In the group of mice treated with PTX from days -2 to 12, the onset of TMEV-IDD was suppressed. On the other hand, in the group of mice treated with PTX from days 14 to 27 or saline, the onset of TMEV-IDD was not inhibited. The results of enzyme-linked immunospot (ELISPOT) assay of spleen cells of mice showed that the production of TNF-alpha and IFN-gamma was significantly inhibited (TNF-alpha and IFN-gamma, p < 0.001) and IL-4 and IL-10 production was significantly increased (IL-4, P < 0.001; and IL-10, P < 0.05, respectively) in the group of mice treated with PTX from days -2 to 12. These findings suggest that PTX suppresses the onset of TMEV-IDD by suppressing the production of TNF-alpha and modulating Th1-dominant immune responses into Th2-dominant ones.
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PMID:The effect of pentoxifylline (PTX) on Theiler's murine encephalomyelitis (TMEV)-induced demyelinating disease. 966 56

Multiple sclerosis is an immune-mediated demyelinating disease of unknown etiology that presents with either a chronic-progressive or relapsing-remitting clinical course. Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) and relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) in the SJL/J mouse are both relevant murine CD4+ T cell-mediated demyelinating models that recapitulate the multiple sclerosis disease phenotypes. To determine the cellular and molecular basis for these observed differences in clinical course, we quantitatively analyzed the temporal expression of pro- and antiinflammatory cytokine mRNA expression in the central nervous system (CNS) and the phenotype of the inflammatory mononuclear infiltrates. TMEV-infected SJL/J mice expressed IFN-gamma, TNF-alpha, IL-10, and IL-4 mRNA during the preclinical phase, and their levels continued to increase throughout the duration of the chronic-progressive disease course. These data correlated with the continued presence of both CD4+ T cells and F4/80+ macrophages within the CNS infiltrates. In contrast, SJL/J mice with PLP(139-151)-induced R-EAE displayed a biphasic pattern of CNS expression for the proinflammatory cytokines, IFN-gamma and TNF-alpha, with expression peaking at the height of the acute phase and relapse(s). This pattern correlated with dynamic changes in the CD4+ T cell and F4/80+ macrophage populations during relapsing-remitting disease progression. Interestingly, IL-4 message was undetectable until disease remission(s), demonstrating its potential role in the intrinsic regulation of ongoing disease, whereas IL-10 was continuously expressed, arguing against a regulatory role in either disease. These data suggest that the kinetics of cytokine expression together with the nature of the persistent inflammatory infiltrates are major contributors to the differences in clinical course between TMEV-IDD and R-EAE.
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PMID:Differential expression of inflammatory cytokines parallels progression of central nervous system pathology in two clinically distinct models of multiple sclerosis. 978 Feb 23

Epitope spreading is a process whereby epitopes distinct from and non-cross-reactive with an inducing epitope become major targets of an ongoing immune response. This phenomenon has been defined in experimental and natural situations as a consequence of acute or persistent infection and secondary to chronic tissue destruction that occurs during progressive autoimmune disease. We have investigated the functional significance of this process in the chronic stages of both autoimmune and virus-induced central nervous system (CNS) demyelinating disease models in the SJL/J mouse. During the relapsing-remitting course of experimental autoimmune encephalomyelitis (R-EAE) induced with defined encephalitogenic myelin peptides, CD4+ T cells specific for endogenous epitopes on both the initiating myelin protein (intramolecular epitope spreading) and distinct myelin proteins (intermolecular epitope spreading) are primed secondary to myelin destruction during acute disease and play a major functional role in mediating disease relapses. Similarly, epitope spreading to endogenous myelin epitopes appears to play a major functional role in the chronic-progressive course of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a virus-induced CD4+ T-cell-mediated immunopathology. In TMEV-IDD, myelin destruction is initiated by virus-specific CD4+ T cells which target virus epitopes persisting in CNS-derived antigen-presenting cells. However, the chronic stage of this progressive disease is associated with the activation of CD4+ T cells specific for multiple myelin epitopes. In both models, the temporal course of T-cell activation occurs in a hierarchical order of epitope dominance, spreading first to the most immunodominant epitope and progressing to lesser immunodominant epitopes. In addition, epitope spreading in R-EAE is regulated predominantly by CD28/B7-1 co-stimulatory interactions, as antagonism of B7-1-mediated co-stimulation using anti-B7-1 F(ab) fragments is an effective ameliorative therapy for ongoing disease. The process of epitope spreading has obvious important implications for the design of antigen-specific therapies for the treatment of autoimmune disease since these therapies will have to identify and target endogenous self epitopes associated with chronic tissue destruction.
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PMID:The functional significance of epitope spreading and its regulation by co-stimulatory molecules. 979 64

We examined the role of IL-12, a cytokine critical to the evolution of cellular responses, in the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Treatment with mAbs to IL-12, especially during the effector phase, resulted in significant suppression of the development of this disease both clinically and histologically. In mice treated with these mAbs, the production of inflammatory and Th1-derived cytokines such as TNF-alpha and IFN-gamma in the spleen cells was decreased, and that of Th2-derived cytokines such as IL-4 and IL-10 was increased. The delayed type hypersensitivity and T cell proliferative response specific for TMEV were decreased by this treatment. These data suggest that IL-12 is critically involved in the pathogenesis of TMEV-IDD and that Abs to IL-12 could be a novel therapeutic approach in the clinical treatment of demyelinating diseases such as human multiple sclerosis.
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PMID:Suppressive effect on Theiler's murine encephalomyelitis virus-induced demyelinating disease by the administration of anti-IL-12 antibody. 982 May 36

Intracerebral inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. We examined the pathogenic roles of nitric oxide (NO) and inducible NO synthase (iNOS) in TMEV-induced demyelinating disease (TMEV-IDD). The presence of iNOS was confirmed in the spinal cords of TMEV-infected mice using immunohistochemical staining with anti-iNOS antibody on day 0 (control) and days 15, 30, 60, and 120. Aminoguanidine (AG), a specific inhibitor of iNOS, was injected intraperitoneally (ip) on 1, 3, 5, 8, 10, and 12 days post-TMEV inoculation as induction phase or 15, 17, 19, 22, 24, and 26 days as effector phase. Control animals in each experiment received phosphate-buffered saline (PBS) ip at similar time intervals. Few iNOS-positive cells were observed in the spinal cords of naive SJL/J mice. In the early phase (day 15) of TMEV-IDD, an increase of iNOS-positive cells was detected in the leptomeninges and perivascular space of the spinal cords. The number of iNOS-positive cells was increased and reached its peak on day 60, when histology of the animals showed peak infiltration with inflammatory cells. The clinical course of TMEV-IDD on each day postintracerebral infection was significantly reduced in mice treated with AG in the effector phase, and there was no significant difference between mice treated with AG in induction phase versus those administered PBS. Thus, NO production via iNOS appears to be a pathogenic factor in the effector phase of TMEV-IDD.
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PMID:Expression and potential role of inducible nitric oxide synthase in the central nervous system of Theiler's murine encephalomyelitis virus-induced demyelinating disease. 1038 21

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) is an excellent model for human multiple sclerosis. Within the BALB/c strain, BALB/cAnNCr mice are susceptible while BALB/cByJ mice are resistant. BALB/cByJ mice become susceptible when irradiated. Adoptive transfer of CD8+ splenic T cells from resistant BALB/cByJ donors protect irradiated BALB/cByJ, as well as BALB/cAnNCr recipients, from development of TMEV-IDD. Anti-TMEV CTL activities in BALB/cAnNCr, BALB/cByJ and irradiated BALB/cByJ mice are comparable. A population of splenic CD4+ T cells in BALB/cByJ donors has also been identified which can protect both susceptible BALB/cAnNCr and irradiated BALB/cByJ recipients from TMEV-IDD via adoptive transfer.
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PMID:The role of protective CD8+ T cells in resistance of BALB/c mice to Theiler's murine encephalomyelitis virus-induced demyelinating disease: regulatory vs. lytic. 1043 47

We examined the role of B7-1 and B7-2, costimulatory molecules critical to full activation of T cells, in the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Treatment with mAbs to B7-1 resulted in significant suppression of the development of this disease both clinically and histologically. In mice treated with these mAbs, the production of TNF-alpha and IFN-gamma in the spleen cells was decreased. The delayed-type hypersensitivity and T cell proliferative response specific for TMEV were decreased by this treatment. In contrast, treatment with Abs to B7-2, resulted in no effect on TMEV-IDD. These data suggest that B7-1 is critically involved in the pathogenesis of TMEV-IDD and that Abs to B7-1 could be a novel therapeutic approach in the clinical treatment of demyelinating diseases such as human multiple sclerosis.
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PMID:Effect of anti-B7-1 and anti-B7-2 mAb on Theiler's murine encephalomyelitis virus-induced demyelinating disease. 1057 Mar 9

Theiler's murine encephalomyelitis virus (TMEV) is a natural mouse pathogen which causes a lifelong persistent infection of the central nervous system (CNS) accompanied by T-cell-mediated myelin destruction leading to chronic, progressive hind limb paralysis. TMEV-induced demyelinating disease (TMEV-IDD) is considered to be a highly relevant animal model for the human autoimmune disease multiple sclerosis (MS), which is thought to be initiated as a secondary consequence of a virus infection. Although TMEV-IDD is initiated by virus-specific CD4(+) T cells targeting CNS-persistent virus, CD4(+) T-cell responses against self myelin protein epitopes activated via epitope spreading contribute to chronic disease pathogenesis. We thus examined the ability of antibodies directed against B7 costimulatory molecules to regulate this chronic virus-induced immunopathologic process. Contrary to previous studies showing that blockade of B7-CD28 costimulatory interactions inhibit the initiation of experimental autoimmune encephalomyelitis, treatment of SJL mice at the time of TMEV infection with murine CTLA-4 immunoglobulin or a combination of anti-B7-1 and anti-B7-2 antibodies significantly enhanced clinical disease severity. Costimulatory blockade inhibited early TMEV-specific T-cell and antibody responses critical in clearing peripheral virus infection. The inhibition of virus-specific immune responses led to significantly increased CNS viral titers resulting in increased damage to myelin-producing oligodendrocytes. Following clearance of the costimulatory antagonists, epitope spreading to myelin epitopes was accelerated as a result of the increased availability of myelin epitopes leading to a more severe chronic disease course. Our results raise concern about the potential use of B7-CD28 costimulatory blockade to treat human autoimmune diseases potentially associated with acute or persistent virus infections.
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PMID:CD28 costimulatory blockade exacerbates disease severity and accelerates epitope spreading in a virus-induced autoimmune disease. 1095 34

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

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


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