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)

Central nervous system (CNS) expression of two chemokine mRNAs, encoding monocyte chemoattractant protein-1 (MCP-1) and IFN-gamma-inducible protein (IP-10), was previously shown to be closely related to the onset of clinical signs of murine experimental autoimmune encephalomyelitis (EAE). Chemokine mRNAs accumulated in a striking, transient burst within astrocytes, near inflammatory leukocyte infiltrates. It remained unclear if chemokines functioned to initiate leukocyte entry into CNS tissues, or to amplify the intrathecal inflammatory reaction. To address this issue, we determined the expression of chemokine mRNAs at the earliest evidence of CNS immune-mediated inflammation. For these experiments, mice were sacrificed in pairs at varying times after immunization. Only one member of each pair was symptomatic for EAE at the time of sacrifice. Symptom presence correlated well with histological inflammation at the time of sacrifice. RNA was prepared from two CNS sites, brain and spinal cord, and expression of chemokine mRNAs was analyzed by a sensitive and quantitative reverse transcriptase/polymerase chain reaction dot-blot hybridization assay. CNS expressions of MCP-1 and IP-10 gene were correlated tightly with histological inflammation; indeed, chemokine expression was never detected in the absence of leukocyte infiltrates. In situ hybridizations showed that astrocytes expressed chemokine transcripts. These findings provide new information about mechanisms controlling chemokine mRNA expression during immune-mediated inflammation in EAE and are consistent with a role for chemokines as amplifiers of CNS inflammatory reactions.
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PMID:Central nervous system chemokine mRNA accumulation follows initial leukocyte entry at the onset of acute murine experimental autoimmune encephalomyelitis. 890 49

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

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 mechanism of action underlying the beneficial effect of IFN-beta in multiple sclerosis (MS) is not understood. To date, little information is available on the effects of IFN-beta in experimental autoimmune encephalomyelitis (EAE), the animal correlate of the human disease MS. Therefore, we investigated the effects of recombinant rat IFN-beta (rrIFN-beta) on EAE in Lewis rats with emphasis on a treatment regimen during the paralytic phase of the disease. The results indicated that rrIFN-beta dose-dependently inhibited disease activity with complete prevention at a s.c. dose of 300,000 U/day, provided that treatment was continued for 3 wk. Discontinuation of treatment on day 17 postimmunization resulted in a protracted and relapsing disease course with strongly enhanced clinical severity. Detailed immunohistology of central nervous system (CNS) tissue of protected animals revealed an almost complete absence of CNS lesions and a >90% reduction in the number of infiltrating leukocytes. Accordingly, isolation of mononuclear cells from spinal cord tissue of successfully treated EAE rats revealed a reduction of approximately 95% in the number of cells that produce IFN-gamma in response to the encephalitogenic peptide MBP63-88. Furthermore, rrIFN-beta significantly enhanced serum corticosterone levels, which showed an inverse relationship with disease activity. We show that rrIFN-beta can have both beneficial and detrimental effects on disease activity dependent on the timing and the duration of treatment. Beneficial effects on EAE are associated with inhibition of the extravasation of blood-derived mononuclear cells in the CNS.
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PMID:The length of treatment determines whether IFN-beta prevents or aggravates experimental autoimmune encephalomyelitis in Lewis rats. 895 26

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

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

Protection against experimental autoimmune encephalomyelitis (EAE) induced by s.c. infusion of myelin basic protein (MBP) alone is dose dependent and long lived. Protection is not effective against passively induced disease nor is it transferable with lymphoid cells. The proliferative response of lymph node cells to MBP following encephalitogenic challenge is decreased in the EAE-protected animals as is the production of IL-2 and IFN-gamma by these cells. Treatment with soluble MBP promed rats for antibody production is evidenced by the early appearance of anti-MBP antibody following encephalitogenic challenge. Determination of antibody isotype following challenge revealed a change in the ratio of IgG1 to IgG2a with a significant increase in the amount of IgG1 produced. These data suggest that infusion of high dose soluble neuroantigen primes the immune response such that subsequent challenge with an encephalitogenic inoculum pushes the response down a non-destructive Th2 autoimmune pathway.
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PMID:Infusion of soluble myelin basic protein protects long-term against induction of experimental autoimmune encephalomyelitis. 904 35

We utilized in situ hybridization to detect expression and regulation of cytolysin mRNA in microglia, astrocytes and oligodendrocytes from newborn rat brains. Expression under natural culture conditions was undetectable or very low, even after 10 days of culture. Cytolysin mRNA expression in microglia, astrocytes and oligodendrocytes was up-regulated by IFN-gamma. This up-regulation in glial cells was slow, and characterized by a gradually increased expression until day 10 of culture. IFN-gamma-mediated up-regulation of cytolysin mRNA was markedly more prominent in oligodendrocytes than in microglia and astrocytes. Unexpectedly, a combination of LPS and IFN-gamma did not exhibit a synergistic effect in the induction of cytolysin mRNA expression in the three types of glial cells. On the contrary, LPS strongly inhibited IFN-gamma-mediated cytolysin mRNA expression in microglia, astrocytes and oligodendrocytes. These results reveal that there may exist a glial cell-dependent cytotoxic pathway within the CNS, and that inducible cytolysin may play an important role in destruction of oligodendrocytes or clearance of infiltrating cells within the CNS in inflammatory diseases such as multiple sclerosis or experimental allergic encephalomyelitis.
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PMID:Induction of cytolysin mRNA in glial cells by IFN-gamma: a possible cytotoxic pathway in the CNS. 905 5

Development of T helper cell (Th)1 or Th2 cytokine responses is essential for effector and regulatory functions of T helper cells. We have compared cytokine profiles of myelin basic protein (MBP) Ac1-16 peptide-specific T helper cells from inbred mouse strains expressing identical k haplotype-derived MHC class II molecules B10.A and B10.BR, B10.BR T cell lines (TCL) produced Th1 cytokines (including high levels of TNF-alpha) and induced experimental autoimmune encephalomyelitis after adoptive transfer. In contrast, B10.A TCL produced Th2 cytokines (including low levels of TNF-alpha) and were poorly encephalitogenic. The contributions of the genetic origin of the T cells and the APC were explored. Serial restimulations of the B10.BR TCL with B10.A or (B10.A x B10.BR) F1 splenic antigen presenting cells (APC) during the establishment of TCL markedly reduced both Th1 cytokine production and encephalitogenicity. In addition, a single restimulation with B10. A splenic APC reduced IFN-gamma and TNF-alpha production by established Th1 MBP-specific Ak-restricted B10.BR TCL and by a Th1 KLH-specific, Ek-restricted B10.BR T cell clone. These studies suggest that B10.A and B10.BR APC differ in their ability to stimulate IFN-gamma and TNF-alpha production by mature Th1 cells and also influence their Th1/Th2 commitment in vivo. The nature of the downregulatory activity of B10.A APC on IFN-gamma and TNF-alpha production was explored. 2-hour supernatants from antigen-activated B10.A APC/TCL cultures or from B10.A APC activated by LPS had the same inhibitory effects on IFN-gamma and TNF-alpha production by B10.BR TCL. The downregulatory effects of B10.A APC are independent of TNF-alpha, IL-4, IL-10, IL-12p40, IFN-gamma, IL-13, TGF-beta, and PGE2. Thus, genetic difference(s) between B10.A and B10.BR APC appear(s) to control the production or activity of a novel soluble cytokine regulatory factor that influences Th1/Th2 commitment and controls production of IFN-gamma and TNF-alpha by mature Th1 cells.
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PMID:Novel genetic regulation of T helper 1 (Th1)/Th2 cytokine production and encephalitogenicity in inbred mouse strains. 905 44

Experimental allergic encephalomyelitis (EAE) is thought to be dominantly mediated by Ag-specific CD4+ MHC class II-restricted T-cells. Recent reports demonstrated accumulation of gammadelta T-cells in active multiple sclerosis (MS) plaque and infiltration into brains with EAE. However, the role of gammadelta T-cells in pathogenesis of EAE remains unknown. In the present study we have examined EAE mice administered T-cell receptor (TCR) gammadelta-specific mAb (UC7-13D5) to elucidate the potential role of gammadelta T-cells in the pathogenesis of EAE. MAb treatment led to transient depleting gammadelta T-cells in vivo. MAb-treated EAE mice showed aggravation and disease recurrence and also increased Ag-specific proliferative responses. Semiquantitative PCR analysis demonstrated an increased level of IFN-gamma mRNA expression in splenocytes from mAb-treated EAE mice during the induction and pre-relapse phase, however, aggravation and disease recurrence have not been suggested to be directly mediated by IFN-gamma in the present study. Our results imply that gammadelta T-cells play a preventing role in the recurrence of EAE.
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PMID:Aggravation of murine experimental allergic encephalomyelitis by administration of T-cell receptor gammadelta-specific antibody. 905 73


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