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)

Impairment of the blood-brain barrier (BBB) in experimental autoimmune encephalomyelitis (EAE) has been frequently attributed to disruption, without much consideration of saturable transport processes. In mice with EAE, we studied the permeability of the BBB to radioactively labeled albumin and sucrose, markers of BBB disruption, and tumor necrosis factor-alpha (TNF-alpha), a cytokine transported across the BBB by a saturable system and thought to play a role in the pathogenesis of EAE. Permeation of the BBB was increased to all three substances during the acutely ill stage, was greatest in the lumbar spine, and returned to normal with recovery. The change in BBB permeability to sucrose was greater than to the larger albumin and is consistent with a partial disruption of the BBB. The enhanced permeability to TNF-alpha was comparable to that for sucrose, even though TNF-alpha is similar in size to albumin. This paradoxically high uptake of TNF-alpha could be explained by an enhancement of its endogenous saturable transport system. Thus the changes in BBB function during EAE extend beyond disruption to include changes in the saturable transport systems for substances involved in the disease process.
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PMID:Differential permeability of the BBB in acute EAE: enhanced transport of TNT-alpha. 889 50

Tumour necrosis factor (TNF) is a highly potent, proinflammatory cytokine with broad-ranging functions from the regulation of endothelial cell adhesion molecules to facilitate entry of leucocytes into tissues, to direct induction of cellular cytotoxicity. This diversity of function potentially attributable to TNF in the genesis of inflammatory disorders place TNF as a primary candidate for clinical targeting and considerable success in this regard has been achieved, particularly in rheumatoid arthritis (RA). In this article we provide a short overview of TNF and its homologue lymphotoxin (LT) alpha and beta. Particular emphasis is placed on recent discoveries regarding the cell surface expression of these cytokines and the role of TNF/LT in experimental autoimmune encephalomyelitis (EAE), an animal model of the human demyelinating disease, multiple sclerosis (MS).
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PMID:Tumour necrosis factor and lymphotoxin: molecular aspects and role in tissue-specific autoimmunity. 891 10

Actively induced experimental autoimmune encephalomyelitis (EAE) in the PL/J mouse is a monophasic disease. We isolated mononuclear cells (MNC) from the central nervous system (CNS), lymph node (LN), blood, and spleen over the course of EAE and counted the number of cells secreting IL-2, IFN-gamma or IL-4 in response to polyclonal stimulation. IL-2 secreting cells were present in the CNS at disease onset but absent at disease peak and at recovery. A profound transient drop in IL-2 secreting cells also occurred in LN, blood, and spleen at disease peak and during recovery. IFN-gamma secreting cell number decreased in all compartments as disease evolved. In contrast, IL-4 secreting cell number was greatest in the CNS at disease peak, i.e. IL-4 secreting cells rose as IL-2 and IFN-gamma secreting cells fell. IL-4 secreting cell number did not change appreciably in LN, blood, and splenic MNC as disease evolved. CNS MNC at disease peak failed to proliferate in response to anti-CD3 mAb but did so in response to IL-2. LN, blood and splenic MNC did proliferate in response to anti-CD3 mAb at disease peak and this proliferation was augmented by exogenous IL-2. After prolonged culture, proliferative response of CNS MNC to anti-CD3 mAb was restored. These results indicate that during monophasic EAE global suppression of naive T cell and Th1 T cell cytokine synthesis occurs but that T cell proliferative responsiveness is selectively inhibited in the CNS.
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PMID:Global inhibition of IL-2 and IFN-gamma secreting T cells precedes recovery from acute monophasic experimental autoimmune encephalomyelitis. 893 74

The costimulatory molecules CD80 and CD86 affect the differentiation of Th1 and Th2 subsets in experimental allergic encephalomyelitis, an autoimmune disorder. It is reported that the CD86 costimulator significantly affects disease outcome in Leishmania major infection, a classic model of Th subset polarization. Treatment of both L. major-resistant (C57BL/6) and susceptible (BALB/c) strains of mice with anti-CD86 substantially decreased parasite burden. This was accompanied, in BALB/c mice, by a decrease in Th2 cytokines. In contrast, anti-CD80 treatment did not affect parasite burden or cytokine levels in either strain. These data illustrate that in L. major infection, anti-CD86 can abrogate Th2 differentiation in a Th2-dominated susceptible mouse and can ameliorate disease in a Th1-dominated resistant strain, although the mechanism involved in the latter is not clear. It is concluded that in L. major infection, Th2 subset differentiation is critically dependent on interaction with the CD86 costimulatory molecule.
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PMID:Blockade of CD86 ameliorates Leishmania major infection by down-regulating the Th2 response. 894 Feb 22

T cells are considered to be of prime importance in immune regulation of both B and T cell functions. The targets of recognition in T-T cell interactions are not clear. Most recent experimental work has focused on the idiotypic regulatory interactions mediated by TCR peptides. There is experimental evidence that regulatory cells exist that do not recognize the TCR. This type of regulation is selectively induced by activated T cells. Therefore, we designed this study to examine the possible role of cytokine receptors as targets of immune regulation. We tested two peptides of IL-2R alpha-chain, 2 of IL-2R beta-chain, and one of TNFR (p60). All peptides were found to be immunogenic at inducing T cell proliferation and four induced Abs in Lewis rats. We generated T cell lines to these five peptides, and tested them both in vitro and in vivo. We found that the T cells exhibited a proliferative response when cultured with activated, irradiated stimulator cells that were augmented upon addition of the cytokine receptor peptide. The cytokine profile of the lines was characterized as well as the Vbeta gene composition. One of the lines significantly protected against active encephalomyelitis. These results point at cytokine receptors as possible targets of immune regulation and T-T cell interactions.
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PMID:IL-2 and TNF receptors as targets of regulatory T-T interactions: isolation and characterization of cytokine receptor-reactive T cell lines in the Lewis rat. 894 88

We previously reported that recovery of Lewis rats from experimental autoimmune encephalomyelitis (EAE) is associated with the appearance of suppressor T cells (Ts). These Ts secrete TGF-beta which down-regulates the production of inflammatory cytokines by the effector T cells that mediate this disease. In the present study, we immunized Lewis rats with myelin basic protein (MBP)+CFA, and evaluated purified T cells and MBP-activated spleen cells (SpC) during the paralytic phase (day 12) and after recovery (days 30-33) for TGF-beta and interferon (IFN)-gamma mRNA. We used reverse transcriptase-polymerase chain reaction (RT-PCR), quantitated on the basis of beta-actin mRNA. Abundant IFN-gamma mRNA was present in MBP-activated SpC obtained on day 12. In contrast, only trace IFN-gamma mRNA was detected in day 30 activated SpC, and no IFN-gamma mRNA was present in purified, nonactivated T cells obtained at either time. The level of IFN-gamma mRNA correlated with secretion of IFN-gamma as determined by ELISA on SpC culture supernatants, and with severity of adoptively transferred EAE by the activated SpC. Thus, it appears that IFN-gamma mRNA is both transcribed and translated in response to antigen activation, resulting in secretion of IFN-gamma by the disease-inducing Te. In contrast, when we used RT-PCR to investigate the expression of TGF-beta mRNA, we found the transcript present in isolated T cells and MBP-activated SpC obtained from rats at both days 12 and 30. The presence of TGF-beta mRNA at time points corresponding to both clinical EAE and recovery suggests post-transcriptional regulation of the production of this immunoregulatory cytokine.
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PMID:Regulation of cytokine gene expression in experimental autoimmune encephalomyelitis. 895 Jul 3

The effect of pentoxifylline (PTX) on experimental allergic encephalomyelitis (EAE) in mice, a known animal model of multiple sclerosis (MS), was investigated. PTX was orally administrated at 10, 40 and 100 mg/kg/day, respectively. Although oral PTX at these doses had no significant effect on the incidence and severity of EAE, oral PTX (40 mg/kg/day) alone produced a significant delay in the onset of EAE. Semiquantitative reverse transcriptase-polymerase chain reaction analysis revealed that PTX at this dose reduced the mRNA levels for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6 in peripheral blood mononuclear cells (PBMC) of mice with EAE. A histopathological study showed that PTX treatment delayed infiltration of inflammatory cells in the central nervous system (CNS) of mice with EAE. These results indicated that the tolerable dose of PTX had a suppressive effect on the induction phase of EAE by modulating cytokine production in PBMC but had no effect on the severity of EAE. The findings in the present study with animals suggested that a tolerable dose of PTX might prolong the intervals between relapses in MS, but might not improve the clinical sign and symptoms of MS.
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PMID:Pentoxifylline delays the onset of experimental allergic encephalomyelitis in mice by modulating cytokine production in peripheral blood mononuclear cells. 895 77

The present study sought to examine the immunopharmacologic effects of suramin on splenocytes from experimental allergic encephalomyelitis (EAE)-induced mice, taken in line with a previous observed action of suramin in ameliorating EAE. Suramin, a polysulfonated napthylurea, decreased the proliferation of T cells, in the presence of various stimuli, such as guinea pig myelin basic protein (MBP), mouse spinal cord homogenate (MSCH), bovine proteolipid protein (PLP), P1 (synthetic peptide 139-151 of PLP), and Mycobacterium tuberculosis (MTB). Suramin inhibited T cell proliferation in a dose-dependent manner. However, cytokine assays revealed that suramin increased antigen-induced levels of IL-4, whilst IFN-gamma levels were decreased. Using various doses of suramin (25, 15, and 5 micrograms/g), its cytokine modulatory effect displayed a consistent dose-dependent activity in vivo. This cytokine modulation commenced on week 2 after immunization and persisted all throughout the drug administration period, up to the 4th week. These results indicate that the prospects of using suramin in the treatment of multiple sclerosis may be feasible.
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PMID:Suramin exerts in vivo cytokine modulatory properties on splenocytes from experimental allergic encephalomyelitis-induced SJL mice: implications for autoimmune disease therapy. 895 79

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

Astrocytes may serve as effectual APCs for T cell-mediated immune responses to myelin components during multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Although astrocytes have been reported not to constitutively express MHC class II molecules, expression is up-regulated during active EAE and by in vitro incubation with IFN-gamma. Previous studies have reported that cytokine-activated astrocytes are able to activate Ag-specific previously activated T cells, but not naive alloreactive T cells. In the current study, we show that a subset of primary murine astrocytes constitutively expresses B7-2 molecules, as determined by FACS and PCR analyses, and up-regulates surface expression and mRNA levels of both B7-2 and B7-1 upon IFN-gamma stimulation. In contrast to earlier reports, we found that both untreated and IFN-gamma-treated astrocytes were able to stimulate proliferation of previously activated OVA-specific Th1 cells. In contrast, only IFN-gamma-treated astrocytes activated naive, transgenic OVA-specific T cells. Astrocyte-induced activation of both OVA-specific naive T cells and activated Th1 cells was dependent primarily on B7-2-mediated costimulation, as proliferation was inhibited by CTLA4-Ig and by anti-B7-2 mAbs. These results suggest that astrocytes in an inflammatory environment have the capacity to express the required MHC class II and B7 costimulatory molecules necessary for efficient activation of naive T cells. Since we have shown that T cells specific for endogenous myelin epitopes released during acute EAE play the major pathologic effector role in subsequent disease relapses (epitope spreading), astrocytes could play a role in the local activation and expansion of these responses.
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PMID:IFN-gamma-activated primary murine astrocytes express B7 costimulatory molecules and prime naive antigen-specific T cells. 899 75


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