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)

Usually we rely on vaccination to promote an immune response to a pathogenic microbe. In this study, we demonstrate a suppressive from of vaccination, with DNA encoding a minigene for residues 139-151 of myelin proteolipid protein (PLP139-151), a pathogenic self-Ag. This suppressive vaccination attenuates a prototypic autoimmune disease, experimental autoimmune encephalomyelitis, which presents clinically with paralysis. Proliferative responses and production of the Th1 cytokines, IL-2 and IFN-gamma, were reduced in T cells responsive to PLP139-151. In the brains of mice that were successfully vaccinated, mRNA for IL-2, IL-15, and IFN-gamma were reduced. A mechanism underlying the reduction in severity and incidence of paralytic autoimmune disease and the reduction in Th1 cytokines involves altered costimulation of T cells; loading of APCs with DNA encoding PLP139-151 reduced the capacity of a T cell line reactive to PLP139-151 to proliferate even in the presence of exogenous CD28 costimulation. DNA immunization with the myelin minigene for PLP-altered expression of B7.1 (CD80), and B7.2 (CD86) on APCs in the spleen. Suppressive immunization against self-Ags encoded by DNA may be exploited to treat autoimmune diseases.
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PMID:Suppressive immunization with DNA encoding a self-peptide prevents autoimmune disease: modulation of T cell costimulation. 1009 87

T cell co-stimulation through the CD28 receptor on T cells is critical to the induction of experimental autoimmune encephalomyelitis (EAE). In this study, expression of the co-stimulatory ligands B7-1 (CD80) and B7-2 (CD86), as well as the receptors CD28 and CTLA-4, were quantitated in central nervous system (CNS) tissues from mice at various stages of EAE. Immunohistochemistry and flow cytometry of CNS-infiltrating cells revealed a high percentage of infiltrating T cells expressing B7-1 and B7-2 during acute, chronic and relapsing EAE. Of the infiltrating cells 10-20% were CTLA-4(+), most of which were CD4(+) T cells. B7-1 and B7-2 expression within the CNS during active EAE might increase the potential for local activation of autoimmune T cells; however, the high level of expression of B7 molecules may also provide a mechanism for the autoregulation of activated CTLA-4(+) T cells.
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PMID:T cells are the main cell type expressing B7-1 and B7-2 in the central nervous system during acute, relapsing and chronic experimental autoimmune encephalomyelitis. 1054 Mar 25

Many types of cells in the immune system have been found to produce nitric oxide (NO), which performs multiplex functions. However, in myelin basic protein peptide 68-86 (MBP 68-86)-induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats, we found that elevated NO production was generated from spleen cells (SC), not from lymph node cells (LNC). LNC expressed lower NO synthase 2 (NOS2) and produced lower levels of NO than SC upon MBP 68-86 stimulation. Expression of B7-1(CD80) and B7-2(CD86) molecules was much lower on LNC than on SC. Blocking of B7-1 or B7-2 ligation resulted in reduced NO production by SC. Unlike SC, LNC were resistant to interferon-gamma- or lipopolysaccharide-induced NO production. NO derived from SC suppressed cell proliferation and induced apoptosis in vitro. Addition of N(omega)-nitrol-L-arginine methylester (L-NAME) into cell cultures promoted cell expansion and reduced apoptosis. These results indicate that NO production originates from SC, but not from LNC. Low expression of co-stimulatory molecules and NOS2 of LNC limits NO induction. The high levels of NO derived from SC are involved in the self-limiting mechanisms of autoimmune responses by inhibiting cell expansion and promoting cell apoptosis.
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PMID:Limitation of nitric oxide production: cells from lymph node and spleen exhibit distinct difference in nitric oxide production. 1072 70

Linomide is a potent immunomodulator that has been shown to inhibit autoimmunity in several animal models of autoimmune disease, including experimental autoimmune encephalomyelitis (EAE). Linomide's mechanism of action is unknown, however, it has been suggested to modulate the function of antigen presenting cells (APC) and that this may account for the inhibition of autoimmune disease. In this study we have been able to show that Linomide treatment of SJL/N mice upregulates the cell surface expression of several activation markers on macrophages and B cells. Thus, we found the following markers, expressed as a % of control, to be significantly upregulated following Linomide treatment; MHC class II (260%), Ly-6A/E (520%), CD11a (280%), CD54 (190%) and CD80 (200%) on macrophages and Ly-6A/E (250%) and CD11a (150%) on B cells. The duration and dosage of Linomide required to obtain these effects is similar to those required for EAE inhibition. Several Linomide analogues were made by the introduction of structural modifications into the Linomide molecule, resulting in a number of compounds with varying effects on EAE. We found a linear relationship between the compound's ability to inhibit EAE and its ability to upregulate MHC class II on macrophages (p<0.001), such that compounds which were able to inhibit EAE also upregulated MHC class II expression, whereas those that did not inhibit EAE were unable to do so. These results suggest that drug-mediated activation of distinct APC functions may be protective in autoimmunity.
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PMID:Inhibition of autoimmune disease by the immunomodulator linomide correlates with the ability to activate macrophages. 1109

We have previously shown that tolerance can be induced against acute experimental autoimmune encephalomyelitis (EAE) in Lewis rats by bone marrow-derived dendritic cells (DC) that have been pulsed in vitro with encephalitogenic myelin basic protein peptide 68-86 (MBP 68-86), and injected subcutaneously into healthy rats prior to immunization with MBP 68-86 plus complete Freund's adjuvant. To elucidate better the properties of tolerogenic DC, we here compared plastic-adherent DC with floating, non-adherent DC, which were cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor plus interleukin-4 (IL-4). Adherent DC expressed high levels of IL-10 mRNA and protein, and low levels of IL-12 mRNA and showed high expression of CD54 compared with floating DC. Proliferation, nitrite concentration and capacity for antigen presentation were lower in adherent DC than in floating DC. There were no differences between adherent and floating DC regarding expression of CD11c, OX62, major histocompatibility complex class II, CD80, or CD86. Most importantly, we observed that adherent DC induced tolerance to EAE in vivo when injected subcutaneously into Lewis rats prior to immunization, while floating DC did not. Adherent DC-mediated tolerance to EAE was associated with augmented proliferation, nitric oxide production and frequency of apoptotic cells as well as with up-regulation of transforming growth factor-beta (TGF-beta) -expressing cells in T-cell areas of lymph nodes. Tolerance induction by adherent DC seems to be related to a nitric oxide-apoptosis pathway and to up-regulation of TGF-beta-expressing cells.
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PMID:Adherent dendritic cells expressing high levels of interleukin-10 and low levels of interleukin-12 induce antigen-specific tolerance to experimental autoimmune encephalomyelitis. 1110 44

Recent evidence suggests that T-lymphocyte extravasation and CNS-parenchymal infiltration during autoimmune disease might be regulated by antigen-presenting (ED2(+)) cerebral/spinal perivascular phagocytes (CPP/SPP). Since the massive erythrocytic and leukocytic infiltrates in the CNS of rats with experimental allergic encephalomyelitis do not allow a precise differentiation between CPP/SPP and the invading cells in the Virchow-Robin space, we developed a new immune-response model whereby the extravasation of T-lymphocytes was not followed by other blood cells. Adult Lewis rats were sensitized to horseradish peroxidase (HRP). Subsequent intracerebroventricular (i.c.v.) injections of HRP and/or Fluoro-Emerald (FE) served to: (1) challenge the primed T-lymphocytes and (2) label the CPP/SPP for additional immunocytochemical analysis. We found that 24 h and 3 days after single, double, or triple antigen boosting T-lymphocytes (R73(+), W3/25(+), OX50(+)) entered the Virchow-Robin space but did not break through the astrocytic glia limitans. Instead they adhered to HRP-containing activated CPP/SPP (mabs OX-6(+), SILK6(+), CD40(+), CD80(+), CD86(+)). This selective contact was mediated neither by cell adhesion molecules (P-selectin, ICAM-1, VCAM-1), nor promoted by chemokine receptors (CCR1, CCR5) or chemokines (monocyte chemoattractant protein (MCP)-1, MIP-1alpha, MIP-1beta, RANTES). This non-inflammatory, but antigen-dependent lymphocyte extravasation provides optimal conditions to further study the CNS immune response.
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PMID:Exogenous antigen containing perivascular phagocytes induce a non-encephalitogenic extravasation of primed lymphocytes. 1143 Oct 2

Some data suggest that the interaction between CD28 and CD80 (B7.1) stimulates Th1-responses and that CD28 and CD86 (B7.2) stimulates Th2-responses, however this is controversial. We addressed this issue by using mercuric chloride (HgCl2)-induced autoimmunity in Brown Norway (BN) rats as a highly polarized Th2 model and experimental autoimmune encephalomyelitis (EAE) in Lewis rats as a highly polarized Th1 model. Monoclonal antibodies (MoAbs) to CD80 and CD86, given singly, had little effect in either model, however when given together they almost completely suppressed the HgCl2-induced autoimmunity: the peak immunoglobulin (Ig)E concentration was 3.25 microg/ml in treated animals versus 2770 microg/ml in controls (P < 0.0001); caecal vasculitis was suppressed with a median vasculitis score of 0 in treated animals versus 6 in controls (P < 0.0001); and new germinal centre formation was significantly suppressed. A combination of the antibodies also markedly reduced the severity of clinical EAE; from a median aggregate clinical score of 9 to 3 (P = 0.02) and delayed the onset from a median of 12.5 days to 16 days after immunization (P = 0.006). We have demonstrated profound suppression of both Th1 and Th2-driven autoimmunity in rats by a combination of anti-CD80 and CD86, but have been unable to demonstrate any clear differential effects.
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PMID:CD80(B7.1) and CD86(B7.2) do not have distinct roles in setting the Th1/Th2 balance in autoimmunity in rats. 1169

Th3 CD4+ regulatory cells were identified during the course of investigating mechanisms associated with oral tolerance. Different mechanisms of tolerance are induced following oral antigen administration, including active suppression, clonal anergy and deletion. Low doses favor active suppression whereas high doses favor anergy/deletion. Th3 regulatory cells form a unique T-cell subset which primarily secretes transforming growth factor (TGF)-beta, provides help for IgA and has suppressive properties for both Th1 and Th2 cells. Th3 type cells are distinct from the Th2 cells, as CD4+ TGF-beta-secreting cells with suppressive properties have been generated from interleukin (IL)-4-deficient animals. In vitro differentiation of Th3 cells from Th precursors from T-cell antigen receptor (TCR) transgenic mice is enhanced by culture with TGF-beta, IL-4, IL-10, and anti-IL-12. Th3 CD4+ myelin basic protein regulatory clones are structurally identical to Th1 encephalitogenic clones in TCR usage, MHC restriction and epitope recognition, but produce TGF-beta with various amounts of IL-4 and IL-10. Because Th3 regulatory cells are triggered in an antigen-specific fashion but suppress in an antigen-non-specific fashion, they mediate "bystander suppression" when they encounter the fed autoantigen at the target organ. In vivo induction of Th3 cells and low dose oral tolerance is enhanced by oral administration of IL-4. Anti-CD86 but not anti-CD80 blocks the induction of Th3 cells associated with low dose oral tolerance. Th3 regulatory cells have been described in other systems (e.g. recovery from experimental allergic encephalomyelitis) but may be preferentially generated following oral antigen administration due to the gut immunologic milieu that is rich in TGF-beta and has a unique class of dendritic cells. CD4+CD25+ regulatory T-cell function also appears related to TGF-beta.
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PMID:Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. 1172 36

The B7:CD28/CTLA-4 costimulatory pathway plays a critical role in regulating the immune response and thus provides an ideal target for therapeutic manipulation of autoimmune disease. Previous studies have shown that blockade of CD28 signaling by mAbs can both prevent and exacerbate experimental autoimmune encephalomyelitis (EAE). In this study, we have designed two CD28 peptide mimics that selectively block B7:CD28 interactions. By surface plasmon resonance, both the end group-blocked CD28 peptide (EL-CD28) and its retro-inverso isomer (RI-CD28) compete effectively with the extracellular domain of CD28 for binding to B7-1. Both the CD28 peptide mimics inhibited expansion of encephalitogenic T cells in vitro. A single administration of EL-CD28 or RI-CD28 peptide significantly reduced disease severity in EAE. Importantly, we show that either CD28 peptide mimic administered during acute disease dramatically improved clinical signs of EAE, suppressing ongoing disease. The ratio of CD80:CD86 expression was significantly lower on CD4(+) and F4/80(+) spleen cells in CD28 peptide-treated mice. Peripheral deletion of Ag-specific CD4(+) T cells occurs following in vivo blockade of CD28 with synthetic CD28 peptides.
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PMID:Suppression of experimental autoimmune encephalomyelitis using peptide mimics of CD28. 1216 48

Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are approved for cholesterol reduction, may also be beneficial in the treatment of inflammatory diseases. Atorvastatin (Lipitor) was tested in chronic and relapsing experimental autoimmune encephalomyelitis, a CD4(+) Th1-mediated central nervous system (CNS) demyelinating disease model of multiple sclerosis. Here we show that oral atorvastatin prevented or reversed chronic and relapsing paralysis. Atorvastatin induced STAT6 phosphorylation and secretion of Th2 cytokines (interleukin (IL)-4, IL-5 and IL-10) and transforming growth factor (TGF)-beta. Conversely, STAT4 phosphorylation was inhibited and secretion of Th1 cytokines (IL-2, IL-12, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha) was suppressed. Atorvastatin promoted differentiation of Th0 cells into Th2 cells. In adoptive transfer, these Th2 cells protected recipient mice from EAE induction. Atorvastatin reduced CNS infiltration and major histocompatibility complex (MHC) class II expression. Treatment of microglia inhibited IFN-gamma-inducible transcription at multiple MHC class II transactivator (CIITA) promoters and suppressed class II upregulation. Atorvastatin suppressed IFN-gamma-inducible expression of CD40, CD80 and CD86 co-stimulatory molecules. l-Mevalonate, the product of HMG-CoA reductase, reversed atorvastatin's effects on antigen-presenting cells (APC) and T cells. Atorvastatin treatment of either APC or T cells suppressed antigen-specific T-cell activation. Thus, atorvastatin has pleiotropic immunomodulatory effects involving both APC and T-cell compartments. Statins may be beneficial for multiple sclerosis and other Th1-mediated autoimmune diseases.
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PMID:The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. 1242 6


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