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)

Multiple sclerosis (MS) is probably caused by multiple factors, but there is evidence that an autoimmunological process is relevant for the pathogenesis. Cytokines can operate in different ways in MS and the animal model "experimental allergic encephalomyelitis (EAE). "Interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), TNF-beta, interleukin-1 (IL-1) and IL-2 are important inflammation mediators within the MS plaque, whereas IFN-alpha, IFN-beta, transforming-growth-factor-beta (TGF-beta) and IL-10 exert mainly immunosuppressive functions. Application of these anti-inflammatory cytokines and the selective block of pro-inflammatory cytokines are promising new therapeutic strategies with fewer side effects than the commonly used cytostatic drugs.
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PMID:[Pathogenesis and therapy of multiple sclerosis. The role of cytokines]. 771 57

Ramified microglia in the adult central nervous system (CNS) are the principal glial element up-regulating MHC class I and II expression in response to inflammatory events or neuronal damage. A proportion of these cells also express MHC class II constitutively in the normal CNS. The role of microglia as APCs for CD4+ T cells extravasating into the CNS remains undefined. In this study, using irradiation bone marrow chimeras in CD45-congenic rats, the phenotype CD45lowCD11b/c+ is shown to identify microglial cells specifically within the CNS. Highly purified populations of microglia and nonmicroglial but CNS-associated macrophages (CD45highCD11b/c+) have been obtained directly from the adult CNS, by using flow cytometric sorting. Morphologically, freshly isolated microglia vs other CNS macrophages are quite distinct. Of the two populations recovered from the normal CNS, it is the minority CD45highCD11b/c+ transitional macrophage population, and not microglia, that is the effective APC for experimental autoimmune encephalomyelitis-inducing CD4+ myelin basic protein (MBP)-reactive T cells. CD45highCD11b/c+ CNS macrophages also stimulate MBP-reactive T cells without addition of MBP to culture, suggesting presentation of endogenous Ag. This is the first study in which microglia vs other CNS macrophages have been analyzed for APC ability directly from the CNS, with substantial cross-contamination between the two populations eliminated. The heterogeneity of these populations in terms of APC function is clearly demonstrated. Evidence is still lacking that adult CNS microglia have the capacity to interact with and stimulate CD4+ T cells to proliferate or secrete IL-2.
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PMID:Normal adult ramified microglia separated from other central nervous system macrophages by flow cytometric sorting. Phenotypic differences defined and direct ex vivo antigen presentation to myelin basic protein-reactive CD4+ T cells compared. 772 89

Resistance to experimental allergic encephalomyelitis (EAE) induction by homogenized myelin (MSCH) in complete Freund's adjuvant (CFA) and pertussigen (P) in SJL mice was seen 1 week after intravenous injection of PLP 139-151 coupled to spleen cells (PLP-ECDI-SP). Although this resistance could be transferred by spleen cells enriched for CD8+ T cells and thus had a component of immunoregulatory T cells, it was primarily due to anergy, as it was reversible by four daily injections of interleukin (II)-2 starting 3 days after the PLP-ECDI-SP. Earlier treatment with IL-2 did not reverse the tolerance. In view of the known higher sensitivity to anergy induction of Th1 than of Th2 cells, a change in the cytokine balance in the response to MSCH+CFA after anergy induction might be responsible for the resistance to EAE induction. The effect of treatment with cytokines alone on induction of EAE was therefore also determined. Short-term (1-2 weeks) daily pretreatment with IL-2 (4000 U) or TGF-beta 2 (1 micrograms) somewhat decreased the susceptibility to subsequent EAE induction, but IL-4 (5 ng), IL-10 (5 micrograms) or IL-12 (50-200 ng) had no effect under those conditions, even if low doses of PLP were injected simultaneously. Daily injections of IL-4 over an 8-week period prior to immunization, however, significantly lowered the incidence of EAE. Simultaneous injections of IFN-gamma (2000 U/day) completely abolished this effect of IL-4. The effect of these cytokines administered immediately after the immunization with MSCH + CFA + P was also examined. As shown earlier, TGF-beta 2 (100-1000 ng/day) caused a marked protection when it was given intraperitoneally on days 5-9 after injection of MSCH + CFA. IL-4 (5 ng/day), in contrast, was very protective when administered on days 0-4 and less so when given on days 5-9 or even on days 0-12. IL-10 (1 microgram/day) was not protective under these conditions and IL-12 (50 ng/day) significantly increased the severity and mortality of EAE when given on days 0-4 after MSCH + CFA.
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PMID:Tolerogenic forms of auto-antigens and cytokines in the induction of resistance to experimental allergic encephalomyelitis. 775 10

Previous reports have shown that tumor necrosis factor (TNF) exerts a role on the physiology of astrocytes under inflammatory situations. The signalling for biological effects of this and other cytokines are usually exerted through cell surface receptors. In this study, we have demonstrated the presence of a surface TNF alpha receptor type I in murine astrocytes of both SJL/J and BALB/c origin, using 125I-labelled recombinant mouse TNF alpha. A linear Scatchard plot indicates the presence of only one type of receptor with a MW of 58 kDa (Type I TNF receptor) that binds the ligand with a Kd of 1 x 10(-9) M. There are 3,000 copies of this receptor on untreated astrocytes. The results also indicate that receptor-bound TNF is rapidly internalized at 37 degrees C and degraded intracellularly to a principal molecular species which elutes from HPLC reverse-phase columns at 38% acetonitrile rather than at 60%, as native TNF alpha does. The binding is up-regulated by increasing the number of receptors (but not its affinity) by treatments with Theiler's murine encephalomyelitis virus (TMEV), Con A and inflammatory cytokines such as IL-1 alpha, IL-6, and INF-gamma. It is not influenced by vaccinia virus, IL-2, or LPS. This receptor may contribute to the initiation of perpetuation of the immune response which mediates the demyelinating inflammation induced by Theiler's virus.
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PMID:The receptor for tumor necrosis factor on murine astrocytes: characterization, intracellular degradation, and regulation by cytokines and Theiler's murine encephalomyelitis virus. 778 4

The inflammatory cytokines IFN-gamma and TNF-alpha have been demonstrated in various autoimmune diseases, and are thought to participate in the induction and pathogenesis of disease. TFN-alpha is a cytopathic cytokine that is cytotoxic for oligodendrocytes in vitro and has been implicated in the pathology of multiple sclerosis and its animal model experimental allergic encephalomyelitis (EAE). We used reverse transcriptase (RT)-PCR to study the kinetics, cellular source, and regulation of cytokine gene expression in the central nervous system (CNS) of SJL/J mice with myelin basic protein-induced EAE at different stages of the disease. The expression of CD3, IL-2, IFN-gamma, and TNF-alpha mRNA was barely detectable in the CNS of unmanipulated mice or mice that were immunized with adjuvant but showed no symptoms. These mRNAs were readily detectable in the CNS of mice during peak disease, then coordinately dropped to background levels during remission. Analysis of cells isolated from the CNS of mice with acute EAE showed that the Th1 cytokines, IL-2 and IFN-gamma, were produced by infiltrating CD4+ T cells. In contrast, TNF-alpha was predominantly transcribed by non-T mononuclear CNS cells, the majority of which were identified as microglia and macrophages by their Mac-1 phenotype. Microglia could be discriminated by their low expression of CD45. Incubation of freshly derived, adult microglia from normal, uninfiltrated, CNS with activated Th1 supernatant induced the production of TNF-alpha mRNA. Therefore, TNF-alpha is made by both CNS-resident microglia and infiltrating macrophages during EAE, and this production is tightly controlled by cytokines secreted by infiltrating CD4+ T cells.
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PMID:TNF-alpha expression by resident microglia and infiltrating leukocytes in the central nervous system of mice with experimental allergic encephalomyelitis. Regulation by Th1 cytokines. 781 94

To examine the complex role of cytokines in the pathogenesis of actively induced murine EAE we measured the levels of a number of cytokines (IL-6, IFN gamma and TNF) in the spinal cord and CSF of mice with active experimental autoimmune encephalomyelitis (EAE) and found them all to be elevated. We next treated mice with antibodies to these three cytokines, which were over expressed in the CNS, to determine if they would alter disease and found the following: anti-IL-6 had no significant effect on disease, anti-IFN gamma exacerbated disease, and anti-TNF either enhanced, had no effect or inhibited EAE depending on the antibody used. We then treated mice with exogenous cytokines, delivered using a recombinant vaccinia virus system, and found that the IL-6 and TNF virus constructs inhibited EAE whereas the IFN gamma construct had no effect on disease. Other cytokine recombinant viruses were also tested and it was found that the IL-1 beta, IL-2 and IL-10 viruses inhibited EAE while an IL-4 virus either had no effect or enhanced disease. We do not know the mechanism of action of the various cytokines in this system, but irrespective of the mechanism(s), this work clearly demonstrates that delivery of select cytokines using recombinant virus-cytokine constructs can provide a powerful means of down-regulating experimental organ-specific autoimmune disease.
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PMID:Cytokines and murine autoimmune encephalomyelitis: inhibition or enhancement of disease with antibodies to select cytokines, or by delivery of exogenous cytokines using a recombinant vaccinia virus system. 782 86

The cytokine effector status of CD4+ T cells from lymph nodes (LN) and the central nervous system (CNS) of SJL/J mice immunized with autoantigen in adjuvant for the induction of experimental allergic encephalomyelitis (EAE) was compared. CD4+ T cells were FACS sorted based on the levels of expression of the activation marker CD45RB. Low levels of expression of this surface marker are induced by antigen recognition and are associated with 'effector' T cell function. Reverse transcriptase polymerase chain reaction (PCR) was used to analyze the expression of different T cell cytokine genes in the sorted populations. CD45RBlow cells constituted a minority of CD4+ cells in the LN and expressed elevated levels of IL-2, IFN-gamma, and IL-4 mRNA, whereas the CD45RBlow CD4+ population did not express detectable message for these cytokines under linear PCR conditions. By contrast to the LN, CD4+ cells from the CNS were predominantly CD45RBlow and expressed readily detectable levels of IL-2 and IFN-gamma mRNA, but almost no IL-4 transcription could be detected. IL-4 mRNA levels in CNS were 100- to 250-fold lower than in LN. Also, IL-4 message could not be detected in the CNS 1 week after remission. A cytokine-specific immunocytochemical single cell staining technique was used to enumerate cytokine-producing cells in LN cell populations and in CNS infiltrates. Between 1 and 5% cells in isolated LN cells produced detectable IL-2 and IFN-gamma. By contrast, the frequency of cytokine-producing cells stained in perivascular infiltrates in frozen sections from the brains of animals with active EAE was 10-fold higher.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective enrichment of Th1 CD45RBlow CD4+ T cells in autoimmune infiltrates in experimental allergic encephalomyelitis. 791 Apr 82

Efficient immunologic tolerance, defined as antigen-specific unresponsiveness, can be peripherally induced by the i.v. injection of syngeneic splenocytes coupled with antigen using ethylene carbodiimide (ECDI). We have previously reported that unresponsiveness induced via i.v. injection of syngeneic splenocytes coupled with intact, UV-inactivated Theiler's murine encephalomyelitis virus (TMEV-SP) resulted in 'split tolerance'. Both virus-specific delayed-type hypersensitivity and IgG2a levels were inhibited, whereas IgG1 levels were increased when compared with sham tolerized controls. In the present report we demonstrate that tolerance induced by i.v. injection of TMEV-coupled splenocytes resulted in antigen-specific inhibition of T cell proliferation, as well as IL-2 and IFN-gamma production in response to both whole TMEV and the immunodominant viral epitope. Additionally, tolerance induction resulted in abrogation of Th1-derived [IL-2, IFN-gamma and LT/tumor necrosis factor-beta (TNF-beta)] cytokine mRNA expression in response to in vitro stimulation with UV-inactivated TMEV as determined by reverse transcriptase polymerase chain reaction. In contrast, expression of Th2-derived (IL-4, IL-6 and IL-10) cytokine mRNA was not affected in tolerized mice. Tolerance functioned directly at the level of CD4+ Th1 cells at both the induction and effector limbs as depletion of CD8+ T cells both prior to in vivo tolerization or in vitro culture had no effect on inhibition of Th1-specific responses. The mechanism of in vivo tolerance induction appeared to be anergy of CD4+ Th1 cells since IL-2, IFN-gamma and LT/TNF-beta mRNA expression as well as virus-specific proliferative responses could be restored by addition of rIL-2 to in vitro cultures of tolerant, CD4+ Th1 populations. These results suggest that in vivo 'split tolerance' induced by i.v. injection of ECDI-fixed, antigen-coupled splenocytes involves anergy of TMEV-specific, CD4+ Th1 lymphocytes and concomitant priming of Th2 cells. The induction of antigen-specific, in vivo anergy has important implications in the design of therapeutic strategies for immunopathologic diseases mediated by Th1 lymphocytes, especially T cell-mediated autoimmune disorders.
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PMID:Anergy in vivo: down-regulation of antigen-specific CD4+ Th1 but not Th2 cytokine responses. 808 Aug 42

There is now increasing evidence that the hormonal form of vitamin D, 1,25(OH)2D3, is involved in the regulation of the immune system. Local production of the hormone in various infectious diseases can benefit the immune environment. 1,25(OH)2D3 exerts most of its actions only after it has bound to its specific nuclear receptor. These receptors are present in monocytes and activated lymphocytes. The hormone inhibits lymphocyte proliferation and immunoglobulin production in a dose-dependent fashion. It also blocks the accumulation of the mRNAs for IL-2, IFN-gamma and GM-CSF. It interferes with T helper cell (Th) function, reducing Th-induction of immunoglobulin production by B-cells and inhibits the passive transfer of cellular immunity by Th in vivo. The steroid hormone promotes suppressor cell activity and inhibits the generation of cytotoxic and NK cells. The expression of Class II antigen by lymphocytes and monocytes is also affected. In vivo, 1,25(OH)2D3 is particularly effective in preventing auto-immune diseases such as experimental auto-immune encephalomyelitis, murine lupus, and diabetes in NOD mice. Synthetic analogues of vitamin D3 that bind to receptors but have no hypercalcemic effect in vivo have recently been developed for therapeutic use.
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PMID:[Vitamin D and the immune system]. 809 May 62

A novel method for the isolation of leukocytes from the spinal cords of mice during chronic relapsing experimental allergic encephalomyelitis (CREAE) was developed using discontinuous density gradients. Immunostaining of these cells, together with spinal cord sections and peripheral blood leukocytes, with a panel of monoclonal antibodies enabled a detailed profile of the kinetics and cell phenotype during CREAE to be developed. Overall, the kinetics of cell accumulation within the spinal cord correlated with disease severity. The number of cells increased from an average of 5 x 10(4) in unimmunized animals to 40 x 10(4) in paralysed animals during the initial disease episode. The cell numbers rapidly declined with clinical remission (6 x 10(4) cells/cord) and again dramatically increased during clinical relapse. Low numbers of CD3+ lymphocytes (50-150 cells) were consistently isolated from normal mice. However, the number of T cells infiltrating the spinal cord increased following immunization. The numbers of T cells, macrophages, B cells, neutrophils, and Ig-bearing cells all paralleled the clinical disease course, with T cells and macrophages (showing evidence of myelin breakdown) predominating. T cells infiltrating the spinal cord generally failed to express gamma delta T cell receptors and expressed low levels of IL-2 receptors (5% of infiltrating T cells). These cells were phenotypically dissimilar to peripheral blood leukocytes isolated in parallel, with the spinal cord having a consistently higher ratio (9:1) of CD4+ to CD8+ than the peripheral blood (7:3). The low expression of MEL-14 (L-selectin) and 16a antigen (CD45RBhigh) and the higher levels of Pgp-1 (CD44) expressed by the infiltrating T cells, compared with splenocytes, suggest a preferential recruitment/retention of distinct T cell subsets, possibly memory/primed cells, into the central nervous system from the periphery during neuroimmunological disease.
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PMID:Isolation and characterization of cells infiltrating the spinal cord during the course of chronic relapsing experimental allergic encephalomyelitis in the Biozzi AB/H mouse. 817 74


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