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)

Memantine, a clinically employed drug with N-methyl-D-aspartate (NMDA) receptor antagonistic effects, dose-dependently ameliorates neurological deficits in Lewis rat experimental autoimmune encephalomyelitis (EAE). Interestingly, this therapeutic effect was not due to dampened CNS inflammation, as assessed by immunohistochemical evaluation of spinal cord tissue. Furthermore, numbers of interferon gamma (IFN gamma) mRNA expressing cells were not decreased, as assessed by in situ hybridization. Systemic immunity in terms of numbers of IFN gamma secreting cells in response to immunodominant myelin basic protein (MBP) peptides ex vivo was not reduced, and non-toxic doses of memantine did not affect lymphocyte proliferation or IFN gamma secretion in vitro. Considering these findings, we hypothesize that effector mechanisms responsible for reversible neurological deficits in EAE may involve NMDA receptors, and this highlights neurons as targets during autoimmune neuroinflammation.
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PMID:Memantine abrogates neurological deficits, but not CNS inflammation, in Lewis rat experimental autoimmune encephalomyelitis. 878 60

Inbred mice exhibit a spectrum of susceptibility to induction of experimental allergic encephalomyelitis (EAE). We have compared the immune responses of the susceptible SJL (H-2s) and resistant B10.S (H-2s) strains to determine factors other than the MHC background which control resistance/susceptibility to EAE. The resistance of the B10.S strain was found to be secondary to an antigen-specific defect in the generation of Th 1 cells that produce IFN gamma. This defect in IFN gamma production could be restored by exposure of the myelin basic protein (MBP)-reactive T cells to IL-12 with the subsequent induction of the ability to transfer EAE to naive recipients. These findings have important implications for the therapeutic use of IL-12 and IL-12 antagonists and may explain the association between relapses/exacerbation of autoimmune disease and infectious diseases.
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PMID:IL-12 unmasks latent autoimmune disease in resistant mice. 878 37

Treatment with the beta 2-adrenergic agonist terbutaline or the beta-adrenergic agonist isoproterenol suppresses experimental allergic encephalomyelitis, decreases the number of IFN gamma-producing splenic cells, and decreases the number of beta-adrenergic receptors on splenic lymphocytes in Lewis rats. The effects of terbutaline are greater when the drug is given from the day of immunization through the acute phase of the illness or from day 15 postimmunization until recovery, than when given for the first 12 days after immunization.
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PMID:Experimental allergic encephalomyelitis, beta-adrenergic receptors and interferon gamma-secreting cells in beta-adrenergic agonist-treated rats. 878 19

In the present study we address the question of whether distinct self-determinants can target alternative autoimmune disease patterns in experimental autoimmune encephalomyelitis (EAE), an animal model widely used for studying multiple sclerosis. We have found that the clinical course of EAE can be determined by the target peptide selected for induction of disease. In SJL/J mice, actively induced and passively transferred EAE mediated by the immunodominant PLP determinants p139-151 and p178-191 consistently produced a rapid onset of severe clinical signs. In contrast, a delayed onset of both active and passive EAE is associated with the nondominant cryptic PLP determinant p104-117. The delayed disease induced with p104-117 is not associated with any unusual peptide feature, with bystander immunoregulation, with inept class II MHC binding, or with failure to induce T cell expression of CD44, VLA-4, or IL-2 receptor upon activation. However, delayed disease is associated with innate qualities of the T cell repertoire responding to the p104-117 determinant. T cell lines responding to the cryptic p104-117 show limited TCR-V beta utilization compared to the diverse repertoire responding to the dominant p139-151 determinant. The repertoire deletions are accompanied by low level production of pathogenic Th1 cytokines (IFN gamma; IL-2) and increased production of regulatory Th2 (IL-4) cytokine in activated p104-117 primed T cells. Thus, the delayed encephalitogenicity of p104-117 may be due to TCR-V beta deletions and activation defects in the responding T cell repertoire. The development of "slow disease" mediated by autoreactivity against hidden self-determinants may have important implications in the pathogenesis of both relapsing and chronic autoimmune demyelinating disease.
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PMID:Determinant-regulated onset of experimental autoimmune encephalomyelitis: distinct epitopes of myelin proteolipid protein mediate either acute or delayed disease in SJL/J mice. 882 78

We have previously demonstrated that type I IFNs administered orally (p.o.) suppress clinical relapse in murine chronic relapsing experimental autoimmune encephalomyelitis (CR-EAE), inhibit clinical attacks at doses equivalent to ineffective parenteral (s.c.) doses in acute rat EAE, and decrease the adoptive transfer of EAE. We therefore examined the optimal clinical p.o. dose of murine species-specific IFN-alpha for suppression of relapse attacks and compared it to s.c. administered IFN-alpha in a dose-response experiment in the chronic EAE model. The optimal clinically effective dose for suppression of EAE of p.o. administered murine species-specific IFN-alpha was 10 units and for s.c. administered was 100 units, although the optimal p.o. dose was much more clinically effective than the optimal s.c. dose. Con A- and MT-induced spleen cell proliferation was inhibited by p.o. IFN-alpha, as was Con A-induced IL-2 secretion, but s.c. IFN-alpha did not inhibit the Con A-induced proliferation in spleen cells. Oral IFN-alpha inhibited the mitogen-induced production of IL-2 and IFN-gamma, but s.c. IFN-alpha increased MT-induced IFN-gamma and IL-6 secretion in spleen cells and Con A-induced IL-6 and MT-induced IL-2 and IL-6 in lymph node cells. The oral route is a convenient drug delivery system that may allow the use of lower doses of cytokines and provide enhanced efficacy via unique and potent immunoregulatory circuits without generating additional inflammatory cytokines that may counteract the beneficial effects of s.c. administered type I IFNs.
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PMID:Oral administration of IFN-alpha is superior to subcutaneous administration of IFN-alpha in the suppression of chronic relapsing experimental autoimmune encephalomyelitis. 884 48

129/Sv mice are resistant to induction of experimental autoimmune encephalomyelitis (EAE) induced with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Mice of this strain lacking the gene coding for the ligand-binding chain of the IFN-gamma receptor develop EAE with high morbidity and mortality. Spleen cells from sensitized IFN-gammaR-/- mice proliferated extensively when stimulated with MOG peptide in culture and produced high levels of IFN-gamma and TNF but no detectable IL-4. Transfer of spleen cells from sensitized IFN-gammaR-/- mice produced EAE in both IFN-gammaR+/+ and IFN-gammaR-/- recipients. Disease was severe in IFN-gammaR-/- recipients and mortality high (77%). Surviving mice remained moribund until termination of the experiments. IFN-gammaR+/+ recipients developed disease of equal severity, but with no mortality, and recovered significantly. These results indicate that IFN-gamma is not essential for the generation or function of anti-MOG35-55 effector cells but does play an important role in down-regulating EAE at both the effector and induction phase of disease.
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PMID:IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. 887 15

Semliki Forest Virus (SFV) causes a more severe acute encephalomyelitis in B6 than in SJL mice despite similar T cell proliferation and antibody responses in these two strains. To determine the immunological mechanisms that may contribute to this difference, CNS tissues from SFV-infected B6 and SJL mice were analyzed for viral replication, inflammatory responses and cytokine production, by semiquantitative reverse transcriptase-PCR and immunohistochemistry. Although initially similar on day 2 p.i., SFV replicated to higher viral titers in B6 than SJL mice on days 4 and 7 p.i. Infectious virus was cleared from both strains by day 10 p.i. There were no differences in numbers of CD4+, CD8+ or MHC class I and II+ inflammatory cells at any time point. Higher levels of IL-4 mRNA, lower levels of TNF-alpha, IL-6, IL-1 beta and IL-2 mRNAs and lower IL-2+ and IFN-gamma+ cells were found in B6. These findings suggest that despite comparable immune responses, different patterns of cytokine production correlated with higher levels of virus in the brains and more severe clinical disease in B6, and more efficient clearance of virus and less severe disease in SJL mice.
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PMID:Production and role of cytokines in the CNS of mice with acute viral encephalomyelitis. 896 4

Cytokines are important mediators in the pathogenesis of central nervous system (CNS) inflammatory diseases including multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE), viral encephalitis and virus induced demyelinating diseases. We have used immunohistochemical techniques to characterize the mononuclear cell infiltrate and cytokine profiles in the CNS following infection of mice with the demyelinating A7(74) strain of Semliki Forest virus (SFV), an important viral model of MS. Mononuclear cell infiltrates in the CNS, first observed at 3 days and maximal during clearance of infectious virus, were comprised predominantly of CD8+ lymphocytes. F4/80+ macrophage/microglia and CD45/B220+ B lymphocytes were most numerous during the subsequent phase of demyelination. CD4+ T-lymphocytes were observed at low levels throughout infection. By immunostaining MHC class I, IL-1beta , IL-3 and TGF beta1 were constitutively expressed in normal mice and were upregulated following infection. MHC class II, IL-1alpha, IL-2, IL-2R, TNF-alpha and IL-6 were strongly upregulated in the CNS of SFV-infected mice and mice with chronic relapsing EAE. The spatial and temporal distribution of these cytokines during the course of disease was analysed. Whereas IL-1alpha, IL-1beta, IL-10, and TGF beta1 were observed on day 3 following infection GMCSF, IL-2 and TNF alpha were first apparent at day 7 when the cellular infiltration in the CNS was most intense. In contrast IFN gamma and IL-6 were first observed on day 10 prior to the demyelination phase of disease. Cytokines in the lesions of demyelination suggest a role in the pathogeneisis of myelin damage. Based on cytokine profiles no clear bias of either a Th1 or Th2 response was observed in the CNS during infection.
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PMID:Characterization of the cellular and cytokine response in the central nervous system following Semliki Forest virus infection. 911 72

Interferon tau is a type I IFN that was originally identified as a pregnancy recognition hormone produced by trophoblast cells. It is as potent an antiviral agent as IFN alpha and IFN beta, but lacks the toxicity associated with high concentrations of these IFNs in tissue culture and in animal studies. We recently showed that IFN tau, like IFN beta, can prevent the development of experimental allergic encephalomyelitis (EAE). We report here that IFN tau prevents EAE in mice by induction of suppressor cells and suppressor factors. Suppressor cells can be induced by IFN tau in tissue culture, and in vivo by either intraperitoneal injection or by oral administration to mice. Incubation of suppressor cells with myelin basic protein (MBP)-sensitized T cells blocked or delayed the MBP-induced proliferation. Further intraperitoneal injection of suppressor cells into mice blocked induction of EAE by MBP. Suppressor cells possessed the CD4 T cell phenotype, and produced soluble suppressor factors that inhibited MBP activation of T cells from EAE mice. The suppressor factors were found to be IL-10 and TGF beta, which acted synergistically to inhibit the MBP activation of T cells from EAE mice. These findings are important for understanding the mechanism(s) by which type I IFNs protect against autoimmune disease.
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PMID:CD4 T suppressor cells mediate interferon tau protection against experimental allergic encephalomyelitis. 914 35

IFN tau is a member of the type I IFN family but unlike IFN alpha and IFN beta, IFN tau lacks toxicity at high concentrations. Recently, ovine IFN tau was shown to prevent acute induction and superantigen reactivation of experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). In this report, we examined the ability of IFN tau when administered by oral feeding to block development of EAE. Oral feeding of INF tau prevented paralysis in the acute form of EAE in NZW mice and chronic-relapsing EAE in SJL/J mice. In addition, oral feeding of IFN tau at 10(5) U/dose was as effective as intraperitoneal (i.p.) injection in preventing chronic-relapsing EAE, and both forms of IFN tau administration resulted in IL10 production. Histological examination revealed no inflammatory lymphocytic infiltration to the CNS in IFN tau treated animals as compared to controls. Prolonged treatment of IFN tau was shown to be necessary for chronic-relapsing EAE since removal of IFN tau treatment by either oral feeding or i.p. injection resulted in onset of disease. Lastly, sera from SJL/J mice which received prolonged IFN tau treatment by oral feeding exhibited little to no development of anti-IFN tau antibodies. Thus, oral feeding of ovine IFN tau may be a successful form of IFN tau administration for treatment of autoimmune diseases such as MS and may circumvent potentially debilitative antibody responses.
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PMID:Oral feeding of interferon tau can prevent the acute and chronic relapsing forms of experimental allergic encephalomyelitis. 914 36


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