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)

Linomide is a synthetic immunomodulator that has been shown to protect animals against a wide range of spontaneously developing or induced autoimmune diseases. We have previously reported that Linomide blocks both the clinical and the histopathological manifestations of experimental autoimmune encephalomyelitis (EAE) in various animal models. In this study, in an effort to elucidate the mechanisms by which Linomide suppresses EAE, and autoimmunity in general, we investigated the in vivo effects of this drug on the TH1/TH2 lymphocyte balance, which is important for the induction or inhibition of autoireactivity. Naive SJL/J mice were treated orally for 15 days with Linomide (80 mg/kg/day). Spleen cells were obtained at various time points during the treatment period and were stimulated in vitro with concanavalin A. Interleukins IL-4, IL-10 and IL-12, transforming growth factor-beta (TGFbeta) and interferon-gamma (IFNgamma) cytokine production was evaluated both by means of detection of the cytokines in the medium (by ELISA technique) and by detection of the cytokine mRNA production, using a semiquantitative reverse transcriptase polymerase chain reaction method. A significant upregulation of IL-4, IL-10 and TGFbeta was observed following treatment with Linomide, which peaked at day 10 (IL-10) or day 15 (IL-4). On the other hand, IL-12 and IFNgamma production were either unchanged or decreased. It seems therefore that Linomide induces in vivo a shift towards TH2 lymphocytes which may be one of the mechanisms of downregulation of the autoimmune reactivity in EAE. Our observations indicate that downregulation of TH1 cytokines (especially IL-12) and enhancement of TH2 cytokine production may play an important role in the control of T-cell-mediated autoimmunity. These data may contribute to the design of new immunomodulating treatments for a group of autoimmune diseases.
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PMID:Linomide downregulates autoimmunity through induction of TH2 cytokine production by lymphocytes. 1036 27

The present study was designed to assess the pattern of cytokine expression over the course of disease in the central nervous system (CNS) of recipients of an encephalitogenic T-cell clone specific for proteolipid protein (PLP) peptide 139-151. Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses of CNS mRNA from samples taken during the onset of acute disease demonstrated upregulation of message for cytokines involved in the recruitment and activation of macrophages (GM-CSF, interleukin (IL)-3, IL-9) and the inflammatory cytokines tumor necrosis factor (TNF)-alpha and iNOS as well as message for IL-10 and transforming growth factor (TGF)beta. During the recovery stage message for most cytokines was absent, but during relapse inflammatory cytokine messages were again detectable. Message for the accessory molecules B7-2 and CTLA-4 was observed only on the day of onset of acute experimental allergic encephalomyelitis (EAE) and at relapse. The messages for these molecules were downregulated at the onset of recovery. These results illustrate the dynamic nature of the immune response during the course of EAE, and support a model of disease in which T-cells are involved in the regulation of disease while a nonspecific inflammatory reaction is responsible for the CNS damage observed during EAE.
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PMID:Pathogenesis of acute passive murine encephalomyelitis II. Th1 phenotype of the inducing population is not sufficient to cause disease. 1037 66

Spontaneous remission of experimental allergic encephalomyelitis (EAE) is usually associated with prominent apoptosis. The mechanisms behind apoptosis are unknown. We examined the functions of dendritic cells (DC) from Lewis rats with EAE induced by immunization with myelin basic protein peptide 68-86 (MBP68 - - 86). Recovery from EAE was associated with three major functional changes of freshly prepared DC: (1) elevated proliferation, (2) increased nitric oxide (NO) production, and (3) augmented IFN-gamma secretion. In Freund's complete adjuvant (FCA)-immunized control rats, no increase of proliferation, NO production or IFN-gamma secretion was observed on day 21 post-immunization (p.i.), i.e., recovery from EAE. In vitro effects of IFN-gamma, TNF-alpha, TGF-beta1, IL-4 and IL-10 on DC were examined. IFN-gamma enhanced proliferation and NO production by DC, while TNF-alpha and IL-4 induced only slight DC proliferation. DC from recovering EAE rats (day 21 p.i.) suppressed MBP68 - - 86-induced T cell proliferation compared to DC obtained at other time points in EAE and FCA-immunized rats. DC-derived NO induced apoptosis of CD4+ T cells, thereby inhibiting autoreactive T cell responses. Besides IFN-gamma stimulation, NO production by DC was mainly induced in an antigen-dependent manner when DC were co-cultured with T cells. The results suggest that spontaneous recovery from EAE is associated with augmented DC functions. Overproduction of NO by DC results in apoptosis of autoreactive CD4+ T cells, thereby decreasing autoreactive T cell reactivities. The existence of such a NO negative feedback loop may contribute to remission of EAE.
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PMID:Mechanisms of recovery from experimental allergic encephalomyelitis induced with myelin basic protein peptide 68-86 in Lewis rats: a role for dendritic cells in inducing apoptosis of CD4+ T cells. 1040 75

Regulation of the immune response is critical to homeostasis. While innate immunity can influence the development of adaptive immune responses, its role in regulation is less well understood. Recently, NK cells have been implicated in the control of experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. In this report, we show that rat bone marrow-derived NK cells exhibited potent inhibitory effects on T cell proliferation to both Con A as well as the central nervous system Ag myelin basic protein. There was also a significant decrease in both IFN-gamma and IL-10 production in vitro, whereas levels of the beta-chemokine monocyte chemoattractant protein-1 were significantly elevated. Flow cytometry studies suggest that the NK cells may play an important role in regulating both normal and autoimmune T cell responses by exerting a direct effect on activated, autoantigen-specific T cells.
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PMID:Inhibition of autoimmune T cell responses in the DA rat by bone marrow-derived NK cells in vitro: implications for autoimmunity. 1041 39

This paper reports that DA rats develop experimental autoimmune encephalomyelitis (EAE) when immunized with encephalitogenic myelin basic protein (MBP) peptide (MBP63-81) in IFA. In contrast, most rodent strains are tolerized by this procedure. Doses as low as 5 micrograms peptide + IFA induced EAE in DA rats. Lewis (LEW) rats did not develop EAE, even after immunization with 100 micrograms encephalitogenic peptide (MBP68-86) + IFA, but were rendered tolerant to EAE. DA rat T cells proliferated to peptide, and proliferation was inhibited by CTLA4Ig, and by anti-B7.1 and anti-B7. 2 mAbs. This indicates that the ease of induction of EAE in this strain does not reflect a decreased requirement for T cell costimulation through the B7/CD28 costimulatory pathway. The inhibitory effect of CTLA4Ig was abrogated in the presence of anti-TGF-beta-neutralizing Ab. An encephalitogenic DA T cell line expressed mRNA for the Th1 cytokines IFN-gamma and TNF-alpha, as well as IL-10, and secreted these cytokines. In contrast, a T cell line from peptide + IFA-immunized LEW rats (which did not develop EAE) failed to secrete these cytokines. Although this line did not express TNF-alpha or IL-10 mRNA, IFN-gamma mRNA was detected, suggesting posttranscriptional regulation of IFN-gamma expression. Attempts to induce unresponsiveness in DA rats with encephalitogenic peptide-coupled splenocytes were also unsuccessful.
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PMID:Strain variation in autoimmunity: attempted tolerization of DA rats results in the induction of experimental autoimmune encephalomyelitis. 1043 7

Experimental allergic encephalomyelitis (EAE) is a T(h)1-type cell-mediated autoimmune disease induced by immunization with myelin proteins and mediated by CD4(+) T cells. Although susceptibility to EAE is dependent largely on MHC background, the B10.S strain is resistant to induction of EAE despite sharing the I-A(s) MHC locus with the susceptible SJL strain. Furthermore, NOD mice which spontaneously develop diabetes are susceptible to EAE induction with myelin oligodendrocyte glycoprotein (MOG) 35-55, whereas a MHC congenic strain, III, which also expresses I-A(g7) MHC haplotype does not develop diabetes and is also resistant to EAE induction. We induced EAE in these four strains of mice with MOG peptides 92-106 (for I-A(s) strains) and 35-55 (for I-A(g7) strains) in complete Freund's adjuvant. In the susceptible strains (SJL and NOD) in vitro, there are high levels of IFN-gamma production, whereas the resistant strains (B10.S or III) secreted primarily IL-4/IL-10 and transforming growth factor (TGF)-beta, and had decreased levels of IFN-gamma. When brains from susceptible and resistant mice were examined by immunohistochemical methods for cytokine expression, the brains from resistant mice showed fewer infiltrates which predominantly expressed IL-4 and IL-10 and/or TGF-beta. Brains from NOD and SJL with EAE showed mainly IL-2 and IFN-gamma positive cells. Thus, resistance to MOG induced EAE in B10.S and III mouse strains is related to non-MHC genes and is associated with an altered balance of pro- and anti-inflammatory cytokines both in lymphoid tissue and in the brain following immunization with myelin antigens.
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PMID:Genetic susceptibility or resistance to autoimmune encephalomyelitis in MHC congenic mice is associated with differential production of pro- and anti-inflammatory cytokines. 1046 78

Possible mechanisms involved in the protective effect of staphylococcal enterotoxin B (SEB) injection on the subsequent development of experimental autoimmune encephalomyelitis (EAE) were investigated. Only partial clonal deletion and anergy of Vbeta8 + T-lymphocytes were documented after myelin basic protein immunization in SEB injected mice. Brain permeability was not influenced. Within the brain or during in vitro rechallenge assays SEB protected mice produced significantly more IL-10, IL-4, TNF-alpha and iNOS. It is suggested that the immune deviating effect of SEB may be involved in its EAE protective effect.
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PMID:Effect of staphylococcal enterotoxin B injection on the development of experimental autoimmune encephalomyelitis: influence of cytokine and inducible nitric oxide synthase production. 1050 70

Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) T cell-mediated, inflammatory disease with similarities to multiple sclerosis in humans. Intranasal (i.n.) administration of a myelin basic protein (MBP)-derived peptide can protect susceptible mice from EAE. The mechanisms underlying this phenomenon, however, remain unclear. To analyze the phenotypic and functional changes taking place during the induction of tolerance by peptide inhalation, we have studied the fate of CD4(+) T cells after i.n. peptide application using transgenic mice expressing a TCR specific for the N-terminal peptide (Ac1-9) of MBP. Peripheral T cell death was variably observed in TCR transgenic mice after a single i.n. administration of antigenic peptide but was transient and incomplete. Transgenic spleen cells and cervical lymph node cells responded with a cytokine burst to peptide inhalation and hyperproliferation when re-stimulated in vitro. Transfer experiments demonstrated that the duration of peptide administration required to induce tolerance depended on the precursor frequency of T cells in recipient animals. The stringency of i.n. peptide treatment was increased so as to test the efficacy of tolerance induction both in vitro and in vivo in the presence of high precursor frequencies of antigen-specific T cells. Multiple i.n. doses of peptide completely protected TCR transgenic mice from EAE induced with myelin. Such repeated peptide administration resulted in down-regulation of the capacity of antigen-specific CD4(+) T cells to proliferate or to produce IL-2, IFN-gamma and IL-4 but increased the production of IL-10. The role of IL-10 in suppression of EAE in vivo was demonstrated by neutralization of IL-10. This completely restored susceptibility to EAE in mice previously protected by i.n. peptide. Considering the immunosuppressive properties of IL-10, T cells which are resistant to apoptosis might act as regulatory cells and mediate bystander suppression.
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PMID:Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10. 1050 80

We here study the adjuvant properties of immunostimulatory DNA sequences (ISS) and coinjected cytokine-coding cDNA in suppressive vaccination with DNA encoding an autoantigenic peptide, myelin basic protein peptide 68-85, against Lewis rat experimental autoimmune encephalomyelitis (EAE). EAE is an autoaggressive, T1-mediated disease of the CNS. ISS are unmethylated CpG motifs found in bacterial DNA, which can induce production of type 1 cytokines in vertebrates through the innate immune system. Because ISS in the plasmid backbone are necessary for efficient DNA vaccination, we studied the effect of one such ISS, the 5'-AACGTT-3' motif, in our system. Treatment with a DNA vaccine encoding myelin basic protein peptide 68-85 and containing three ISS of 5'-AACGTT-3' sequence suppressed clinical signs of EAE, while a corresponding DNA vaccine without such ISS had no effect. We further observed reduced proliferative T cell responses in rats treated with the ISS-containing DNA vaccine, compared with controls. We also studied the possible impact of coinjection of plasmid DNA encoding rat cytokines IL-4, IL-10, GM-CSF, and TNF-alpha with the ISS-containing DNA vaccine. Coinjection of IL-4-, IL-10-, or TNF-alpha-coding cDNA inhibited the suppressive effect of the DNA vaccine on EAE, whereas GM-CSF-coding cDNA had no effect. Coinjection of cytokine-coding cDNA with the ISS-deficient DNA vaccine failed to alter clinical signs of EAE. We conclude that the presence of ISS and induction of a local T1 cytokine milieu is decisive for specific protective DNA vaccination in EAE.
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PMID:Presence of CpG DNA and the local cytokine milieu determine the efficacy of suppressive DNA vaccination in experimental autoimmune encephalomyelitis. 1052 74

NO and IFN-gamma have normally been considered cytotoxic and proinflammatory molecules, respectively, in the setting of the central nervous system inflammatory disease autoimmune encephalomyelitis (EAE). Using mice lacking the ligand binding chain of the IFN-gamma receptor (IFNgammaR-/-), we have previously shown that IFN-gamma is not essential for myelin oligodendrocyte glycoprotein peptide (MOG35-55) induced EAE expression but is in fact essential for its down-regulation. Here we examined the downstream molecular and cellular mechanism(s) of IFN-gamma regulation and demonstrate that neither IL-4 nor IL-10 appear to play a role in down-regulation nor do various lymphoid cell populations. Cells of the macrophage lineage are key to down-regulation as evidenced by the fact that peritoneal exudate cells from IFNgammaR+/+ mice inhibit Ag-driven proliferation of IFNgammaR-/- lymphocytes, whereas IFNgammaR-/- peritoneal exudate cells do not. High levels of reactive nitrogen intermediates are detected in the former cultures but not the latter, and the inhibition of proliferation is reversible with an inhibitor of inducible NO synthase, indicating a key role for NO in down-regulation. Studies with bone marrow chimeras indicate that down-regulation occurs not only systemically but also within the target tissue. These data suggest that IFN-gamma down-regulates EAE by inducing inducible NO synthase and subsequently NO production, both by macrophages in the periphery and, by inference, microglia and astrocytes in the target tissue.
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PMID:IFN-gamma is critical to the control of murine autoimmune encephalomyelitis and regulates both in the periphery and in the target tissue: a possible role for nitric oxide. 1055 50


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