UMLS:C0014070 - FACTA Search

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Query: UMLS:C0014070 (encephalomyelitis)
13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upregulated expression of the low-affinity neurotrophin receptor (p75) in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE) has recently been demonstrated. To investigate whether p75 plays a role in disease pathogenesis, we adopted a gene therapy approach, utilizing antisense oligonucleotides to downregulate p75 expression during EAE. Phosphorothioate antisense oligonucleotides (AS), nonsense oligonucleotides (NS) or phosphate buffered saline (PBS) were injected daily for 18 days after immunization of SJL/J (H-2s)-mice with myelin proteolipid protein (PLP) peptide 139-151. In the AS group, there was a statistically significant reduction in both the mean maximal disease score (1.85 in the AS, 2.94 in the NS and 2.75 in the PBS-groups, respectively, P < 0.025) and in the cumulative disease incidence ( approximately 60% in the AS group and approximately 90% in the control groups). Histological and immunohistochemical analysis showed reduced inflammation and demyelination, as well as reduced p75 expression at the blood-brain barrier (BBB) in the AS-treated mice in comparison with both control groups. There was no difference, however, in p75 expression on neural cells within the CNS between the three groups of mice. We conclude that p75 could play a proactive role in the pathogenesis of EAE and may exert its effect at the level of the BBB.
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PMID:Treatment of experimental autoimmune encephalomyelitis with antisense oligonucleotides against the low affinity neurotrophin receptor. 1070 8

The apoptosis-inducing effects of i.v. methylprednisolone were investigated as a possible method of controlling inflammation in the CNS in adoptive transfer-experimental autoimmune encephalomyelitis (AT-EAE) in Lewis rats. Two pulses of methylprednisolone were given at the peak of mild and of severe disease. T-cell apoptosis was assessed on spinal cord cross-sections by morphology and TUNEL staining. Concentrations of methylprednisolone were measured in serum, CSF and spinal cord tissue by high-pressure liquid chromatography (HPLC). In severe EAE, 10 mg/kg methylprednisolone increased T-cell apoptosis significantly and T-cell infiltration was marginally decreased. A maximal dose of 50 mg/kg methylprednisolone was superior in both respects and, in contrast to 10 mg/kg methylprednisolone, was also effective in mild EAE. A dose of 1 mg/kg methylprednisolone did not produce notable changes compared with controls treated with phosphate-buffered saline. Serum, CSF and spinal cord concentrations of methylprednisolone measured by HPLC 2 h after a single i.v. injection of 10 or 50 mg/kg methylprednisolone revealed significantly higher methylprednisolone concentrations in severe EAE compared with mild disease. With 50 mg/kg methylprednisolone, we obtained serum and CSF concentrations in the region of 10(-5) M methylprednisolone. We also studied the expression of bcl-2, a typical anti-apoptotic regulatory protein, in T cells, and found no change after methylprednisolone treatment compared with controls. Methylprednisolone did not induce apoptosis of oligodendrocytes, which would have been an unwanted side effect in CNS cells. This study provides evidence that methylprednisolone dose-dependently augments T-cell apoptosisin situ in AT-EAE. Our results may have implications for the use of glucocorticosteroids at very high doses in the treatment of inflammatory disorders of the CNS, such as multiple sclerosis, or of other target organs.
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PMID:T-cell apoptosis in situ in experimental autoimmune encephalomyelitis following methylprednisolone pulse therapy. 1086 55

Phosphosugars, such as mannose-6-phosphate (M6P), have been shown previously to display anti-inflammatory properties, notably inhibition of experimental autoimmune encephalomyelitis (EAE) and adjuvant-induced arthritis in rats. It has been proposed that M6P exerts its anti-inflammatory effect by displacing lysosomal enzymes, which are involved in T-cell extravasation into inflammatory sites, from the 300 kDa mannose-6- phosphate receptor (MPR-300) on the surface of T cells. If this model is correct MPR-300 should be selectively expressed on the surface of activated T cells, as T cell entry into the central nervous system in EAE depends on the T cells being in an activated state. Thus, the present study examines whether cell surface expression of MPR-300 by T lymphocytes correlates with their state of activation and whether T cells in inflammatory sites express the receptor. Flow cytometric studies showed MPR-300 to be absent from the surface of unstimulated rat T cells isolated from peripheral blood and lymphoid tissues, and T cells resident within the peritoneal cavity. In contrast, MPR-300 was expressed on activated T cells derived from an inflammatory peritoneal exudate. In vitro studies demonstrated transient expression of MPR-300 on the surface of splenic T cells following stimulation with Con A. MPR-300 was also induced on T-cell lines by antigen stimulation. These data demonstrate that T cells in inflammatory sites express MPR-300 on their surface and activation of T lymphocytes induces cell surface expression of MPR-300. Such findings are consistent with the hypothesis that cell surface MPR-300 is required for the entry of T cells into inflammatory sites.
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PMID:Cell surface expression of the 300 kDa mannose-6-phosphate receptor by activated T lymphocytes. 1156 51

Injection of antigen into the testis has been previously proved to induce systemic tolerance in rats. Testicular-associated immune deviation (TAID) has thus far been induced and studied only in the rat and the present study was planned to study if TAID could be induced in mice as well. In addition, it was studied if TAID is organ-specific. Mouse spinal cord homogenate (MSCH), as well as phosphate-buffered saline (PBS), was injected into the testes of SJL and BALB/c male mice before the induction of experimental allergic encephalomyelitis into the animals. The control animals received MSCH intramuscularly into the hamstring muscles. The animals were followed and graded daily for symptoms attending the next 30 days. In the SJL strain, mice treated with an intratesticular (i.t.) MSCH injection prior to the induction of experimental autoimmune encephalomyelitis (EAE) had the shortest duration of symptoms and the longest time to the onset of the first symptoms. In addition, the mice injected i.t. with PBS had as mild symptoms as those injected with MSCH. There was a statistically significant difference, however, between the groups injected either with MSCH or PBS intratesticularly. In general, mice treated with an intramuscular injection of MSCH got sick first, and had the most severe symptoms for the longest duration of time. In the case of the BALB/c mice, there were no statistical differences between the groups investigated. It is concluded that TAID is a testis- and strain-specific phenomenon in the mouse, and not specific to the rat. In addition, i.t. injection of PBS is just as effective in creating tolerance against EAE as i.t. injection of MSCH in the SJL mice.
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PMID:Testicular-associated immune deviation: flushing of the testicular lymph sinusoids induces immunosuppression and inhibits formation of EAE in SJL mice. 1197 59

The chemokine RANTES is critically involved in neuroinflammation and has been implicated in the pathophysiology of multiple sclerosis. We examined the possibility that activation of G-protein-coupled metabotropic glutamate (mGlu) receptors regulates the formation of RANTES in glial cells. A 15 hr exposure of cultured astrocytes to tumor necrosis factor-alpha and interferon-gamma induced a substantial increase in both RANTES mRNA and extracellular RANTES levels. These increases were markedly reduced when astrocytes were coincubated with l-2-amino-4-phosphonobutanoate (l-AP-4), 4-phosphonophenylglycine, or l-serine-O-phosphate, which selectively activate group III mGlu receptor subtypes (i.e., mGlu4, -6, -7, and -8 receptors). Agonists of mGlu1/5 or mGlu2/3 receptors were virtually inactive. Inhibition of RANTES release produced by l-AP-4 was attenuated by the selective group III mGlu receptor antagonist (R,S)-alpha-methylserine-O-phosphate or by pretreatment of the cultures with pertussis toxin. Cultured astrocytes expressed mGlu4 receptors, and the ability of l-AP-4 to inhibit RANTES release was markedly reduced in cultures prepared from mGlu4 knock-out mice. This suggests that activation of mGlu4 receptors negatively modulates the production of RANTES in glial cells. We also examined the effect of l-AP-4 on the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. l-AP-4 was subcutaneously infused for 28 d by an osmotic minipump that released 250 nl/hr of a solution of 250 mm of the drug. Detectable levels of l-AP-4 ( approximately 100 nm) were found in the brain dialysate of EAE rats. Infusion of l-AP-4 did not affect the time at onset and the severity of neurological symptoms but significantly increased the rate of recovery from EAE. In addition, lower levels of RANTES mRNA were found in the cerebellum and spinal cord of EAE rats infused with l-AP-4. These results suggest that pharmacological activation of group III mGlu receptors may be useful in the experimental treatment of neuroinflammatory CNS disorders.
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PMID:Activation of group III metabotropic glutamate receptors inhibits the production of RANTES in glial cell cultures. 1209 92

Cytosolic phospholipase A2alpha (cPLA2alpha) preferentially hydrolyzes phospholipids containing arachidonic acid and plays a key role in the biosynthesis of eicosanoids. This review discusses the essential features of cPLA2alpha regulation and addresses new insights into the functional properties of this enzyme. Full activation of the enzyme requires Ca2+ binding to an N-terminal C2 domain and phosphorylation on serine residues. Ca2+ binding induces translocation of cPLA2alpha from the cytosol to the perinuclear membranes. Serine phosphorylation is mediated by mitogen-activated protein kinases (MAPKs), Ca2+/calmodulin-dependent protein kinase II, and MAPK-interacting kinase Mnk1. Interaction with proteins and lipids, which include vimentin, annexins, NADPH oxidase, phosphatidylcholine, phosphatidylinositol 4,5-bisphosphate (PIP2), and ceramide-1-phosphate, can also modulate the activity of cPLA2alpha. Recent evidence has established the physiological and pathological roles of cPLA2alpha using cPLA2alpha knockout mice. This enzyme has been implicated in fertility, striated muscle growth, renal concentration, postischemic brain injury, arthritis, inflammatory bone resorption, intestinal polyposis, pulmonary fibrosis, acute respiratory distress syndrome, and autoimmune encephalomyelitis. Now novel three paralogs, cPLA2beta, cPLA2gamma, and cPLA2delta, have been identified in humans. cPLA2gamma is distinct from others in that it is farnesylated and lacks the C2 domain. Biological roles for these new enzymes have not yet been defined.
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PMID:Regulatory mechanism and physiological role of cytosolic phospholipase A2. 1530 15

Signaling by sphingosine 1-phosphate (S1P) through its receptor S1P(1) has recently been shown to promote thymocyte egress. In the periphery, S1P(1) is expressed on naive T cells but lost upon T cell activation. To determine the significance of S1P(1) down-regulation and function of S1P(1) in peripheral T cells, we developed transgenic mice that constitutively express S1P(1) in T cells. Mature T cells from these mice exhibited enhanced chemotactic response toward S1P, and preferentially distributed to the blood rather than secondary lymphoid organs. S1P(1)-transgenic mice showed significant delay in the onset of experimental autoimmune encephalomyelitis, and had defective contact hypersensitivity reaction and local Ag-induced responses. These impairments were associated with reduced numbers of Ag-activated T cells in the draining lymph nodes. Our studies demonstrate that S1P(1) signaling affects systemic trafficking of peripheral T cells and immune responses and highlight that levels of S1P(1) expression represent an important mechanism of immune regulation.
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PMID:Cutting edge: regulation of T cell trafficking and primary immune responses by sphingosine 1-phosphate receptor 1. 1572 52

We investigated the treatment of remitting-relapsing experimental autoimmune encephalomyelitis (EAE) in mice with human bone marrow stromal cells (hBMSCs). hBMSCs were injected intravenously into EAE mice upon onset of paresis. Neurological functional tests were scored daily by grading clinical signs (score 0-5). Immunohistochemistry was performed to measure the transplanted hBMSCs, cell proliferation (bromodeoxyuridine, BrdU), oligodendrocyte progenitor cells (NG2), oligodendrocytes (RIP), and brain-derived neurotrophic factor (BDNF). The maximum clinical score and the average clinical scores were significantly decreased in the hBMSC-transplanted mice compared to the phosphate-buffered-saline-treated EAE controls, indicating a significant improvement in function. Demyelination significantly decreased, and BrdU(+) and BDNF(+) cells significantly increased in the hBMSC-treated mice compared to controls. Some BrdU(+) cells were colocalized with NG2(+) and RIP(+) immunostaining. hBMSCs also significantly reduced the numbers of vessels containing inflammatory cell infiltration. These data indicate that hBMSC treatment improved functional recovery after EAE in mice, possibly, via reducing inflammatory infiltrates and demyelination areas, stimulating oligodendrogenesis, and by elevating BDNF expression.
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PMID:Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. 1590 21

FTY720, a sphingosine 1-phosphate receptor modulator, induces a marked decrease in the number of peripheral blood lymphocytes and exerts immunomodulating activity in various experimental allograft and autoimmune disease models. In this study, we evaluated the effect of FTY720 and its active metabolite, (S)-enantiomer of FTY720-phosphate [(S)-FTY720-P] on experimental autoimmune encephalomyelitis (EAE) in rats and mice. Prophylactic administration of FTY720 at 0.1 to 1 mg/kg almost completely prevented the development of EAE, and therapeutic treatment with FTY720 significantly inhibited the progression of EAE and EAE-associated histological change in the spinal cords of LEW rats induced by immunization with myelin basic protein. Consistent with rat EAE, the development of proteolipid protein-induced EAE in SJL/J mice was almost completely prevented and infiltration of CD4(+) T cells into spinal cord was decreased by prophylactic treatment with FTY720 and (S)-FTY720-P. When FTY720 or (S)-FTY720-P was given after establishment of EAE in SJL/J mice, the relapse of EAE was markedly inhibited as compared with interferon-beta, and the area of demyelination and the infiltration of CD4(+) T cells were decreased in spinal cords of EAE mice. Similar therapeutic effect by FTY720 was obtained in myelin oligodendrocyte glycoprotein-induced EAE in C57BL/6 mice. These results indicate that FTY720 exhibits not only a prophylactic but also a therapeutic effect on EAE in rats and mice, and that the effect of FTY720 on EAE appears to be due to a reduction of the infiltration of myelin antigen-specific CD4(+) T cells into the inflammation site.
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PMID:FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. 1642 94

Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease. Chemokine receptor CCR5 has been shown to be essential for the T-cell recruitment to the inflammatory site in EAE. In this study, we assumed that an immunotoxin directed at CCR5+ cells would be able to reduce the disease activity of EAE. A recombinant immunotoxin, DT390-RANTES-SRalpha, was constructed in an eukaryotic cell expression plasmid consisting of regulated on activation normal T cells expressed and secreted (RANTES) as the targeting moiety and DT390 as the toxic moiety. DT390-RANTES was expressed in vitro and was highly toxic to activated mouse T cells with the inhibitory concentration 50 at 0.18 ng/ml. To evaluate whether DT390-RANTES was effective in preventing EAE, C57BL/6 mice were immunized with myelin basic protein, emulsified with complete Freund's adjuvant and were treated by injecting cationic liposome-embedded plasmid DNA into the muscle of hind limbs. Mice treated with DT390-RANTES-SRalpha developed a much milder EAE compared to mice treated with phosphate-buffered saline or the empty plasmid DNA. Much less CCR5+-infiltrating cells were found in the central nervous system in DT390-RANTES-SRalpha-treated mice than in the control mice. This study indicates that recombinant immunotoxin can be expressed in vivo, and targeting CCR5 can attenuate the disease activity of EAE in mice.
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PMID:Prevention of murine experimental autoimmune encephalomyelitis by in vivo expression of a novel recombinant immunotoxin DT390-RANTES. 1670 76

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