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)

Relapsing experimental autoimmune encephalomyelitis (R-EAE) in the SJL mouse is a Th1-mediated autoimmune demyelinating disease model for human multiple sclerosis and is characterized by infiltration of the central nervous system (CNS) by Th1 cells and macrophages. Disease relapses are mediated by T cells specific for endogenous myelin epitopes released during acute disease, reflecting a critical role for epitope spreading in the perpetuation of chronic central CNS pathology. We asked whether blockade of the CD40-CD154 (CD40L) costimulatory pathway could suppress relapses in mice with established R-EAE. Anti-CD154 antibody treatment at either the peak of acute disease or during remission effectively blocked clinical disease progression and CNS inflammation. This treatment blocked Th1 differentiation and effector function rather than expansion of myelin-specific T cells. Although T-cell proliferation and production of interleukin (IL)-2, IL-4, IL-5, and IL-10 were normal, antibody treatment severely inhibited interferon-gamma production, myelin peptide-specific delayed-type hypersensitivity responses, and induction of encephalitogenic effector cells. Anti-CD154 antibody treatment also impaired the expression of clinical disease in adoptive recipients of encephalitogenic T cells, suggesting that CD40-CD154 interactions may be involved in directing the CNS migration of these cells and/or in their effector ability to activate CNS macrophages/microglia. Thus, blockade of CD154-CD40 interactions is a promising immunotherapeutic strategy for treatment of ongoing T cell-mediated autoimmune diseases.
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PMID:Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154) antibody in an animal model of multiple sclerosis. 991 40

SJL mice are susceptible to inflammatory autoimmune diseases of the central nervous system (CNS), while BALB/c mice are relatively resistant. To understand differences in immune responses that may contribute to autoimmune neurologic disease, we compared the responses of SJL and BALB/c mice to infection with Sindbis virus, a virus that causes acute nonfatal encephalomyelitis in both strains of mice. Clearance of virus was similar, but SJL mice developed a more intense inflammatory response in the brain and spinal cord and inflammation persisted for several weeks. Analysis of lymphocytes isolated from brains early after infection showed an absence of NK cells in SJL mice, while both strains of mice showed CD4+ and CD8+ T cells. During the second week after infection, CD4+ T cells increased in SJL mice and the proportion of CD8+ T cells decreased, while the opposite pattern was seen in BALB/c mice. Expression of IL-10 mRNA was higher and IL-4 mRNA was lower in the brains of infected SJL than in BALB/c mice, while expression of the mRNAs of IL-6, IL-1beta, TNFalpha, and the Th1 cytokines IL-2, IL-12, and IFN-gamma was similar. Lymphocytes isolated from the CNS of SJL mice produced large amounts of IL-10. CNS lymphocytes from both strains of mice produced IFN-gamma in response to stimulation with Sindbis virus, but not in response to myelin basic protein. These data suggest that IL-10-producing CD4+ T cells are differentially recruited to or regulated within the CNS of SJL mice compared with BALB/c mice infected with Sindbis virus, a characteristic that may be related to low levels of IL-4, and is likely to be involved in susceptibility of SJL mice to CNS inflammatory diseases.
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PMID:The inflammatory response to nonfatal Sindbis virus infection of the nervous system is more severe in SJL than in BALB/c mice and is associated with low levels of IL-4 mRNA and high levels of IL-10-producing CD4+ T cells. 997 22

Mononuclear cells were isolated from the central nervous system (CNS), lymph nodes (LN), spleen and blood, over the course of murine monophasic experimental autoimmune encephalomyelitis (EAE). Individual cytokine secreting T cells were enumerated. IL-2-secreting alphabeta T cells were numerous at all sites at disease onset. By disease peak their numbers had fallen profoundly; they remained low thereafter. IL-2 secreting gammadelta T cells were rare throughout. IFN-gamma-secreting cells were plentiful at all sites at disease onset. gammadelta T cells comprised 7% of total and 20% of IFN-gamma-secreting CNS-derived cells at disease onset; values at disease peak were 12 and 40% respectively. IL-4-secreting alphabeta T cells were rare in the CNS and LN throughout and did not increase in the spleen from baseline values. In contrast, splenic IL-4-secreting gammadelta T cells had increased to four-fold baseline values at disease onset and seven-fold at disease peak. Recovery from EAE is associated with a global inhibition of IL-2-secreting alphabeta T cells and to a lesser extent with IFN-gamma-secreting alphabeta and gammadelta T cells, whereas IL-4-secreting gammadelta T cells increase in the spleen as disease evolves.
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PMID:Cytokine secretion by deltagamma and alphabeta T cells in monophasic experimental autoimmune encephalomyelitis. 1004 27

The activity of copolymer 1 (Cop 1, Copaxone, glatiramer acetate) in suppressing experimental autoimmune encephalomyelitis (EAE) and in the treatment of multiple sclerosis patients when injected parenterally has been extensively demonstrated. In the present study we addressed the question of whether Cop 1 can induce oral tolerance to EAE similar to myelin basic protein (MBP). We now have demonstrated that oral Cop 1 inhibited EAE induction in both rats and mice. Furthermore, oral Cop 1 was more effective than oral MBP in suppressing EAE in rats. The beneficial effect of oral Cop 1 was found to be associated with specific inhibition of the proliferative and Th1 cytokine secretion responses to MBP of spleen cells from Cop 1-fed mice and rats. In all of these assays, oral Cop 1 was more effective than oral MBP. The tolerance induced by Cop 1 could be adoptively transferred with spleen cells from Cop 1-fed animals. Furthermore, Cop 1-specific T cell lines, which inhibit EAE induction in vivo, could be isolated from the above spleen cells. These T cell lines secrete the anti-inflammatory cytokines IL-10 and transforming growth factor type beta, but not IL-4, in response to both Cop 1 and MBP. In conclusion, oral Cop 1 has a beneficial effect on the development of EAE that is associated with down-regulation of T cell immune responses to MBP and is mediated by Th2/3 type regulatory cells. These results suggest that oral administration of Cop 1 may modulate multiple sclerosis as well.
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PMID:Immunomodulation of experimental autoimmune encephalomyelitis by oral administration of copolymer 1. 1009 37

Molecular mimicry refers to structural homologies between a self-protein and a microbial protein. A major epitope of myelin basic protein (MBP), p87-99 (VHFFKNIVTPRTP), induces experimental autoimmune encephalomyelitis (EAE). VHFFK contains the major residues for binding of this self-molecule to T cell receptor (TCR) and to the major histocompatibility complex. Peptides from papilloma virus strains containing the motif VHFFK induce EAE. A peptide from human papilloma virus type 40 (HPV 40) containing VHFFR, and one from HPV 32 containing VHFFH, prevented EAE. A sequence from Bacillus subtilis (RKVVTDFFKNIPQRI) also prevented EAE. T cell lines, producing IL-4 and specific for these microbial peptides, suppressed EAE. Thus, microbial peptides, differing from the core motif of the self-antigen, MBPp87-99, function as altered peptide ligands, and behave as TCR antagonists, in the modulation of autoimmune disease.
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PMID:Microbial epitopes act as altered peptide ligands to prevent experimental autoimmune encephalomyelitis. 1020 44

Myelin basic protein (MBP)-specific T lymphocytes from male SJL mice were shown to be less encephalitogenic than MBP-specific T lymphocytes from females. Mechanisms underlying this gender difference in the induction phase of EAE were examined. Following immunization with MBP, draining lymph nodes contained fewer cells, and Ag-specific proliferative responses were decreased in males as compared with females. These gender differences in the proliferative response were not unique to MBP-specific responses since they were also observed after immunization with hen eggwhite lysozyme. Short-term MBP-specific T cell lines derived from females and males mapped with identical specificity, indicating no defect in the ability of male APCs to process Ag. Interestingly, IL-12 and IFN-gamma production was decreased following Ag-specific stimulation of draining lymph node cells (LNC) from males as compared with females, but IL-10 and IL-4 were no different. While male-derived LNCs were less encephalitogenic than female derived LNCs, cotransfer and coculture of male LNCs with female LNCs demonstrated that male LNCs were not immunosuppressive. Administration of IL-12 to LNCs from male mice enhanced encephalitogenicity. These data indicate that deficient endogenous IL-12 production within draining LNCs of male SJL mice is central to gender differences in the induction phase of experimental autoimmune encephalomyelitis.
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PMID:Decreased IL-12 production underlies the decreased ability of male lymph node cells to induce experimental autoimmune encephalomyelitis. 1022 38

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

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

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

Antiinflammatory cytokines such as transforming growth factor beta1 (TGF-beta1) and interleukin 4 (IL-4) can protect from autoimmune diseases. To study the immunoregulatory effects of these cytokines in vivo, we used a method of gene therapy that permits continuous cytokine delivery over a period of weeks. We injected naked plasmid DNA expression vectors encoding either TGF-beta1 (pVR-TGF-beta1) or an IL-4-IgG1 chimeric protein (pVR-IL-4-IgG1) intramuscularly. This resulted in production of TGF-beta1 or IL-4-IgG1, respectively, and protection from myelin basic protein (MBP)-induced experimental allergic encephalomyelitis (EAE). TGF-beta1 gene delivery had pronounced downregulatory effects on T cell proliferation and production of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha), on in vitro restimulation with MBP. IL-4-IgG1 vector administration also suppressed these responses, although much less than TGF-beta1, and enhanced secretion of endogenous IL-4. Therapy resulted in a significant decrease in the severity of histopathologic inflammatory lesions. In the CNS, treatment with either vector suppressed IL-12 and IFN-gamma mRNA expression, while IL-4 and TGF-beta1 mRNA levels were increased compared with control mice. Thus, cytokine plasmid treatment appeared to inhibit MBP-specific pathogenic Thl responses, while enhancing endogenous secretion of protective cytokines. We demonstrate that gene therapy with these vectors is an effective therapeutic strategy for EAE.
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PMID:Prevention of experimental allergic encephalomyelitis by intramuscular gene transfer with cytokine-encoding plasmid vectors. 1046 25


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