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)

Experimental allergic encephalomyelitis (EAE) was generated in SJL and B10.PL mice by using the synthetic myelin basic protein peptides. Inflammation in brain and spinal cord preceded clinical signs of disease. Infiltrating lymphocytes were predominantly Lyt1+ (CD5+), L3T4+ (CD4+) T cells, until day 18. After that, F4/80+ monocyte/macrophages outnumbered T cells. Ia+ cells were microglia, macrophages, and endothelial cells, but Ia was not detectable on astrocytes in this EAE model. Ia+ endothelial cells appeared later in the disease than Ia+ microglia and macrophages, suggesting that antigen presentation at the blood-brain barrier is not initially responsible for inflammation. Cells staining for interferon gamma, interleukin 2 (IL-2), and IL-2 receptors were more prominent than IL-4, IL-5, lymphotoxin (LT), and tumor necrosis factor alpha (TNF-alpha), which occurred transiently in the second week and were associated with fewer cells. TNF-alpha and LT were never seen in spinal cord, suggesting that these cytokines are not responsible for initiation of clinical disease. Few or no cells stained for IL-6, IL-1, or transforming growth factor beta. Control animals injected with complete Freund's adjuvant in saline or control antigen demonstrated no inflammatory cell infiltration or cytokine production. Thus, our findings suggest a peptide-induced EAE model in which Th1 T-cell-macrophage interactions result in the disease process.
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PMID:Inflammatory leukocytes and cytokines in the peptide-induced disease of experimental allergic encephalomyelitis in SJL and B10.PL mice. 137 May 83

T cell sensitization to two myelin components, myelin basic protein (MBP) and myelin proteolipid protein (PLP), may be important to the pathogenesis of multiple sclerosis (MS). Using the limiting dilution assay, we demonstrated that the blood of MS patients had an increased frequency of MBP-reactive T cells compared with normal subjects and patients with other neurological diseases (OND) and rheumatoid arthritis. There was no difference in T cell frequency to a synthetic peptide, PLP139-151, or Herpes simplex virus. Within cerebrospinal fluid (CSF), 37% of IL-2/IL-4-reactive T cell isolates from MS patients responded either to MBP or PLP139-151 while only 5% of similar isolates from OND patients responded to these myelin antigens. The mean relative frequency of MBP-reactive T cells within CSF from MS patients was significantly higher than that of OND patients (22 x 10(-5) cells versus 1 x 10(-5) cells) and was similar to that of MBP reactive T cells within the central nervous system of rats with experimental autoimmune encephalomyelitis. These results lend new support to the hypothesis that myelin-reactive T cells mediate disease in MS.
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PMID:Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis. 137 22

We have previously demonstrated that CD4+ suppressor T cells (Ts) inhibit the secretion of interferon (IFN)-gamma, but not interleukin (IL)-2, by effector cells of experimental autoimmune encephalomyelitis (EAE). Moreover, CD4+ Ts appear to regulate IFN-gamma by secretion of transforming growth factor-beta. We now show that CD4+ Ts produce a lymphokine with IL-4 activity in response to a determinant associated with EAE effector cells. CD4+ Ts do not proliferate or secrete IFN-gamma, IL-2, or IL-4 in response to myelin basic protein, nor do CD4+ Ts proliferate or secrete IL-2 when co-cultured with irradiated EAE effector cells. Rather, CD4+ Ts secrete IL-4 when co-cultured with either irradiated effector spleen cells or irradiated encephalitogenic line cells. CD4+ Ts do not secrete IL-4 in response to OVA-primed spleen cells, suggesting that the suppressor cells recognize a determinant specific to encephalitogenic T cells. Furthermore, CD4+ Ts secrete IL-4 when cultured with synthetic T cell receptor (TcR) V beta 8, but not TcR V beta 14 peptide, in the presence of antigen-presenting cells. This response is major histocompatibility complex class II restricted as demonstrated by inhibition of the response with anti-class II monoclonal antibody. These results suggest that CD4+ Ts recognize a determinant associated with TcR on the surface of EAE effector cells and respond by secreting IL-4, in a manner analogous to the Th2 lymphocyte subtype.
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PMID:CD4+ suppressor cells of autoimmune encephalomyelitis respond to T cell receptor-associated determinants on effector cells by interleukin-4 secretion. 137 16

Experimental autoimmune encephalomyelitis (EAE) in the Lewis rat is a self-limited inflammatory process localized to the central nervous system that is induced by the injection of myelin basic protein (MBP) in adjuvant. Oral administration of MBP suppresses EAE, and this suppression is mediated by CD8+ T cells that adoptively transfer protection and suppress both in vitro and in vivo by the release of transforming growth factor (TGF) beta after antigen-specific triggering. Furthermore, oral tolerance to MBP is enhanced by the concomitant oral administration of lipopolysaccharide (LPS). The present study was undertaken to determine whether the disease course in EAE and its suppression by oral tolerization to MBP is associated with distinct patterns of cytokine expression in the target organ. Detailed immunohistology of the brain was performed at the peak of clinical disease (day 14 after immunization) and after recovery (day 18) in control (ovalbumin [OVA]-fed), MBP-fed, and MBP plus LPS-fed animals. Brains from OVA-fed animals at the peak of disease showed perivascular infiltration with activated mononuclear cells which secreted the inflammatory cytokines interleukins (IL) 1, 2, 6, 8, TNF-alpha, and interferon gamma. The inhibitory cytokines TGF-beta and IL-4, and prostaglandin E2 (PGE2) were absent. In MBP orally tolerized animals there was a marked reduction of the perivascular infiltrate and downregulation of all inflammatory cytokines. In addition, there was upregulation of the inhibitory cytokine TGF-beta. In MBP plus LPS orally tolerized animals, in addition to upregulation of TGF-beta and reduction of inflammatory cytokines, there was enhanced expression of IL-4 and PGE2, presumably secondary to activation of an additional population of immunoregulatory cells. In OVA-fed animals that had recovered (day 18), staining for inflammatory cytokines diminished, and there was the appearance of TGF-beta and IL-4. These results suggest that suppression of EAE, either induced by oral tolerization or that which occurs during natural recovery is related to the secretion of inhibitory cytokines or factors that actively suppress the inflammatory process in the target organ.
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PMID:Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. 138 85

Experimental autoimmune encephalomyelitis (EAE) serves as an important animal model for understanding the events that lead to immune-mediated inflammation and tissue destruction within the central nervous system. We have utilized a murine adoptive transfer model of EAE and semiquantitative reverse transcriptase-polymerase chain reaction analysis to examine cytokine mRNA expression within the central nervous system in relation to the onset and resolution of paralysis associated with EAE. Spinal cord samples, obtained from mice as they progressed through discrete clinical stages of EAE, were examined for the expression of six cytokine genes (IL-1 alpha, IL-2, IL-4, IL-6, IL-10, and IFN-gamma). Distinct patterns of cytokine gene expression were observed during the acute, recovery, and chronic phases of EAE. The acute phase of disease was characterized by rapid increases in the levels of mRNA for IL-2, IL-4, IL-6, IFN-gamma, and IL-1 alpha. In fact, peak expression of several cytokine mRNA (e.g., IL-2, IL-4, IL-6, and IFN-gamma) occurred before the peak in clinical severity. In contrast, IL-1 alpha mRNA levels were elevated throughout the initial disease course. IL-10 mRNA demonstrated only modest increases during the acute phase of EAE. Stabilization of the clinical symptoms was characterized by rapid declines in the mRNA levels of IL-2, IL-4, IL-6, and IFN-gamma. The decreases in these four cytokine mRNA levels occurred concomitant with a dramatic rise in IL-10 mRNA. Finally, of the six cytokine mRNA examined, only IL-1 alpha, IFN-gamma, and IL-10 mRNA remained elevated during the early chronic stage. These results suggest that local cytokine production varies significantly during the course of EAE and that increases in discrete sets of cytokines are associated with the acute response and the recovery/chronic phase of disease.
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PMID:Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. 152 89

T cell lines to myelin basic protein (MBP) developed following in vitro culture cause experimental allergic encephalomyelitis (EAE) upon transfer into naive recipient mice. We have, however, repeatedly observed that MBP-specific T cell lines lose their ability to transfer EAE after 40 days in culture. Analyses of such cell lines failed to show any differences in their proliferative responses to antigen, or in the secretion of interleukin-2 (IL-2) and/or IL-4 when compared to their encephalitogenic counterparts. In contrast, examinations of T cell receptor (TCR) beta-chain gene rearrangement patterns showed sequential changes in the clonal population of cells concomitant with the loss of encephalitogenic function. Furthermore, transfer of a non-encephalitogenic, genotypically altered cell line after long-term in vitro culture into mice challenged with MBP suppressed the development of EAE. These findings suggest that the development of such putative regulatory cells in vivo may be involved in the recovery in EAE.
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PMID:Spontaneous development in vitro of a myelin basic protein-specific suppressor T cell line. 247 59

A cytokine-mediated excessive increase in nitric oxide (NO) by macrophages or glial cells via an inducible isoform of NO synthase (iNOS) has been proposed to play an important role in demyelinating diseases. To further investigate the role of iNOS in demyelination, experimental allergic encephalomyelitis (EAE), a known animal model of multiple sclerosis (MS) in mice, was chosen in this study. A semiquantitative reverse transcriptase-polymerase chain reaction (RT/PCR) analysis revealed an increase in the mRNA levels of iNOS and cytokines known to induce iNOS or inflammatory cytokines (interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-6, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and TNF-beta) in the spinal cord corresponding to the severity of the disease without significant change in the mRNA levels of immunoregulatory cytokines (IL-4, IL-10 and transforming growth factor (TGF)-beta) during the course of EAE. An immunohistochemical examination of the spinal cord using an iNOS-specific antibody showed iNOS-positive cells to be mainly inflammatory cells with a higher frequency of iNOS-positive cells at the peak of EAE than in the early phase. These iNOS-positive cells at the peak appeared to be composed of infiltrating macrophages and most of them were located in the necrotic area. These results suggested that cytokine-induced excessive NO via iNOS by macrophages caused tissue damage in the central nervous system in EAE.
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PMID:Expression of the inducible isoform of nitric oxide synthase in the central nervous system of mice correlates with the severity of actively induced experimental allergic encephalomyelitis. 749 86

Polymorphism of the major histocompatibility complex (MHC) influences susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (MBP) in rats. Current concepts relate such influences to the capacity of class II molecules to present relevant peptides to autoreactive T cells. We have here analyzed the MHC influence on the immune response and the development of EAE after immunization with the immunodominant peptide MBP-63-88. Analysis of MHC-congenic LEWIS strains showed that RT1a, RT1c and RT1(1) haplotypes are permissive for disease induction, whereas RT1d and RT1u are resistant. All EAE responding strains showed peptide-specific proliferation and interferon (IFN)-gamma secretion, but no early significant tendency to express interleukin (IL-4) or transforming growth factor (TGF)-beta mRNA in lymphocytes in response to the MBP 63-88, 7 days post immunization (p.i.). Later, 14 days p.i., peptide-specific induction of IL-4 and TGF-beta occurred in RT1(1) rats. Among the EAE non-responders strains, only the RT1u rats showed an immune response to MBP 63-88. This response, however, was qualitatively different from the immune response in the EAE-susceptible strains. Thus, there was no proliferation and only moderate IFN-gamma production in response to peptide, but in contrast, a significant and early peptide-induced IL-4 and TGF-beta response was observed. The data suggest that the MHC-associated susceptibility to EAE is partly related to the ability to mount a TH1-like immune response while the MHC-associated EAE resistance may either be related to MBP peptide non-responsiveness or to peptide recognition and induction of a qualitatively different and disease down-regulatory immune response.
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PMID:The major histocompatibility complex influences myelin basic protein 63-88-induced T cell cytokine profile and experimental autoimmune encephalomyelitis. 750 88

The anti-CD4 mAb W3/25 inhibits experimental autoimmune encephalomyelitis (EAE) in Lewis rats by blocking Th cell responses to encephalitogenic determinants of myelin basic protein (MBP). However, it has yet to be resolved how W3/25 modulates CD4 to inhibit EAE-associated T cell responses. This study revealed that W3/25 profoundly inhibited MBP-stimulated proliferation by sensitized lymph node cells but only partially inhibited the respective response of uncloned and cloned lines of MBP-specific T cells. That is, low concentrations of W3/25 blocked 30 to 60% of MBP-stimulated proliferation, but 100-fold higher concentrations did not result in additional inhibition. W3/25 also inhibited MBP-induced acquisition of EAE transfer activity, but only in cultures of freshly isolated lymph node cells and not in cultures of continuously propagated T cells. Studies focusing on the GP2.E5 T cell line revealed that the lack of sensitivity to W3/25 in encephalitogenic and proliferative assays was nevertheless associated with an effective blockage of MBP-stimulated IL-2 production. Importantly, W3/25 specifically inhibited antigenic but not mitogenic stimulation of IL-2 production. Reverse transcriptase/polymerase chain reaction analyses revealed that MBP-activated GP2.E5 T cells produced mRNA for both IL-2 and IL-4, and that W3/25 selectively inhibited accumulation of IL-2 as compared to IL-4 mRNA. Thus, GP2.E5 T cells apparently express a IL-4-dependent pathway that confers resistance to the inhibitory activity of W3/25. Studies focusing on two CD4+ T cell hybridomas revealed that W3/25 profoundly inhibited MBP-stimulated IL-2 production but did not affect the alternative response of MBP-induced growth inhibition. Several other hybrids also mediated MBP-stimulated IL-2 production but did not express CD4 and were not affected by W3/25. These results indicate that: 1) interactions of W3/25 with CD4 do not necessarily block class II MHC-restricted recognition of MBP; and 2) expression of CD4 is not necessary for Ag recognition by several clonotypes of MBP-reactive T cells. Rather, the results of this study are consistent with the concept that W3/25 inhibits transduction of costimulatory signals that are required specifically for initiation of IL-2 production. These findings may have important implications for understanding the therapeutic potential of anti-CD4 mAb in autoimmune disease.
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PMID:Differentiation of encephalitogenic T cells confers resistance to an inhibitory anti-CD4 monoclonal antibody. 750 25

The biased expression of V beta 5.2 and V beta 6.1 by T cells specific for myelin basic protein (BP) has led to our use of TCR peptides from these V gene sequences to induce anti-TCR immunity in patients with multiple sclerosis (MS). Injection of V beta 5.2-39-59 or V beta 6.1-39-59 peptides significantly increased the peptide specific T cell frequency in 7 of 11 MS patients, often with an accompanying delayed hypersensitivity reaction at the injection site. Here, we validate these cellular immune responses by characterizing TCR peptide specific T cells from an MS patient with biased V beta 5.2 expression in BP reactive T cells before treatment with TCR peptides, and from two MS patients in whom the frequencies of anti-TCR peptide specific T cells were significantly boosted after injection with low doses of TCR peptides. In both cases, T cell lines were established with relative ease, especially after boosting with the peptides. A V beta 5.2-39-59 reactive line responded selectively to the boosting peptide and was restricted by both MHC class I (HLA-B7) and MHC class II (HLA-DR2) molecules. Characterization of 22 clonal isolates revealed that the responding T cells were predominantly activated CD4+CD8lo, circulating memory cells restricted by either HLA-B7 or HLA-DR2, that utilized mainly V beta 4, V beta 6, V beta 12, and V beta 14, but not V beta 5.2 in their TCR. T cell isolates specific for V beta 6.1-39-59 possessed similar characteristics but contained specificities cross-reactive with an N-terminal sequence on V beta 5.2-39-59. Upon stimulation with peptide or Con A, the TCR peptide specific T cell lines had increased message production for IFN-gamma, GM-CSF, IL-4, IL-5, and to a lesser degree, IL-2. This lymphokine mRNA profile differed from a BP-specific T cell line that produced message for IFN-gamma and GM-CSF but low or absent levels of IL-4 and IL-5. The extensive parallels between human T cells specific for V beta 5.2 and V beta 6.1 CDR2 peptides and rat T cells specific for V beta 8.2 CDR2 peptide that are highly protective against experimental encephalomyelitis strengthen the rationale for the therapeutic use of TCR peptides in human autoimmunity.
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PMID:Immunity to TCR peptides in multiple sclerosis. II. T cell recognition of V beta 5.2 and V beta 6.1 CDR2 peptides. 751 Jul 47


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