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)

T cell extravasation into perivascular tissue during inflammation involves transmigration through the endothelial cell (EC) layer and basement membrane. We have demonstrated that matrix metalloxproteinase-2 (MMP-2) is induced in T cells upon adhesion to endothelial cells and that the induction of MMP-2 is mediated by binding of T cell VLA-4 to VCAM-1. Cloned murine Th1 cells antigenic to myelin basic protein, either expressing VLA-4 on their cell surface and causing experimental autoimmune encephalomyelitis (EAE) or not expressing VLA-4 and not causing EAE, were used. VLA-4 positive (+) T cells that adhered to VCAM-1 positive (+) endothelial cells exhibited an induction in MMP-2 mRNA, protein, and activity, whereas MMP-2 was not induced in the T cells that adhered to the VCAM-1 negative (-) endothelial cells or VLA-4 negative (-) T cells that adhered to VCAM-1+ endothelial cells. Incubating T cells with rVCAM-1-coated dishes showed that VLA-4+ T cells adhered to the molecule and that adhesion to rVCAM-1 was sufficient to induce MMP-2. VLA-4+ T cells that had transmigrated through a VCAM-1+ endothelial cell monolayer exhibited MMP-2 activity. TIMP-2 was shown to reduce T cell transmigration in vitro. Transmigrated T cells exhibited downregulation of VLA-4 and LFA-1 integrin surface expression and decreased binding to rVCAM-1 and rICAM-1 and increased binding to collagens I and IV, fibronectin, and laminin. Brain sections of mice demonstrated that as T cells migrated farther into the tissue, VLA-4 expression was lost, although CD4 expression remained unchanged. These results demonstrate that binding to VCAM-1 on endothelial cells induces MMP-2 in T cells, which, in turn, may facilitate T cell migration into perivascular tissue. The significance of these findings in the modulation of the inflammatory response is discussed.
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PMID:The roles of adhesion molecules and proteinases in lymphocyte transendothelial migration. 916 45

We examined the role of leukocyte function-associated antigen (LFA)-1 and its counter-receptor intercellular adhesion molecule (ICAM)-1, one of the most important pairs of adhesion molecules, in the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Immunohistochemical study showed hyper-expression of ICAM-1 on vascular endothelial cells and expression of LFA-1 on mononuclear infiltrating cells in the spinal cords of TMEV-infected mice. Treatment with mAb to ICAM-1 and/or LFA-1 molecules resulted in significant suppression of the development of demyelinating disease, both clinically and histologically, with down-regulation in the CNS of the respective adhesion molecules after treatment. In mice treated with these mAb, the specific delayed-type hypersensitivity and T cell proliferative responses for TMEV were decreased. The production of tumor necrosis factor-alpha and IFN-gamma in spleen cells was also decreased, but IL-4 production remained unchanged. These data suggest that ICAM-1/LFA-1 interaction is critically involved in the pathogenesis of TMEV-IDD and that antibodies to these adhesion molecules could be a novel therapeutic approach to the treatment of demyelinating diseases such as human multiple sclerosis.
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PMID:Anti-adhesion molecule therapy in Theiler's murine encephalomyelitis virus-induced demyelinating disease. 946 11

The effect of a novel TNF binding protein (TNFbp), a polyethylene glycol-linked form of the type I soluble receptor of TNF, on the expression of adhesion molecules has been investigated with a passive transfer model of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice. The expression of L-selectin, VLA-4 and LFA-1 on spleen cells of EAE animals treated with TNFbp or saline was examined by FACS analysis. The expression of VCAM-1 and ICAM-1 was investigated by immunochemistry in spinal cord tissue of SJL/J mice with EAE. In animals sensitized for EAE and treated with TNFbp, the expression of VCAM-1 in the central nervous system as well as VLA-4 on spleen cells was clearly diminished. Reduction in VCAM-1 staining and VLA-4 expression corresponded to inhibition of inflammation in the spinal cord and to prevention of clinical signs of EAE. The results have also shown that myelin basic protein responses as well as non-antigen-specific responses were not diminished in animals treated with TNFbp. The findings suggest that TNFbp might prevent EAE development by modulating the expression of VCAM-1 and VLA-4.
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PMID:Suppression of experimental autoimmune encephalomyelitis with a TNF binding protein (TNFbp) correlates with down-regulation of VCAM-1/VLA-4. 964 85

Intercellular adhesion molecule (ICAM)-1, or CD54, is a member of the immunoglobulin superfamily that binds to lymphocyte function-associated antigen-1 and macrophage-1 antigen. ICAM-1:LFA-1/Mac-1 interaction may be involved in both activation and extravasation of leukocytes. To determine the roles of ICAM-1 in the development of autoimmune disease, we studied experimental autoimmune encephalomyelitis (EAE) in mice deficient in ICAM-1. We found that T cell proliferation and TH1-type cytokine production in response to myelin antigen were significantly reduced in ICAM-1-deficient mice, whereas TH2-type cytokine IL-10 was increased. Unexpectedly, EAE induced by either myelin oligodendrocyte glycoprotein or myelin basic protein was significantly enhanced in mice deficient in ICAM-1. The enhancement was evidenced primarily by the increase in disease severity, mortality, and the degree of central nervous system inflammation. The cellular composition of the inflammatory infiltrates in the central nervous system is similar in control and ICAM-1-deficient mice. These results suggest that (1) ICAM-1 is involved in the activation of autoreactive TH-1, but not TH2 cells, and (2) ICAM-1 plays an important role in down-regulating autoimmune inflammation in the central nervous system.
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PMID:Experimental autoimmune encephalomyelitis in intercellular adhesion molecule-1-deficient mice. 982 50

We have examined the interferon-gamma (IFN-gamma) induced increase in lymphocyte adhesion to rat brain endothelial cells (BEC) in the experimental allergic encephalomyelitis (EAE) susceptible LEW and resistant PVG strain. A significant increase in adhesion of mitogen activated lymphocytes could be demonstrated by stimulating LEW BEC with 50 U/ml IFN-gamma for 24 h. In contrast the same treatment failed to induce a significant increase in lymphocyte adhesion in the PVG strain. Flow cytometric analysis of lymphocyte integrin expression indicated a marked increase in the number of cells expressing both LFA-1 and VLA-4 following mitogen activation and was similar between the LEW and PVG strain. Depletion of LFA-1 and VLA-4 positive lymphocytes resulted in an equivalent inhibition of adhesion to BBB-EnC indicating that the adherent population was comprised predominantly of the VLA-4 + /LFA-1 + phenotype. We conclude that this strain variation in the IFN-gamma activation of BEC may be related to the disease phenotypes of these strains.
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PMID:Strain specific variation in IFN-gamma inducible lymphocyte adhesion to rat brain endothelial cells. 984 16

CD45 is involved in the regulation of lymphocyte activation, and it has been demonstrated that ligation of CD45 induces apoptosis of T and B lymphocytes. Recently anti-CD45RB antibody therapy was shown to block acute allograft rejection in a mouse model of transplantation. Therefore, we wanted to examine the effects of anti-CD45RB antibody treatment on the course of an autoimmune disorder, experimental allergic encephalomyelitis (EAE), a Th1-mediated process. Mice immunized with myelin basic protein and treated with anti-CD45RB antibody did not develop EAE. Histologically, there was no evidence of lymphocytic infiltrates in the central nervous system. T cell proliferation and TNF-alpha production were significantly decreased in anti-CD45RB-treated mice. Furthermore, there was a significant reduction in the production of other Th1 cytokines including interferon-gamma and IL-2, but not IL-4 or IL-6. However, levels of a number of adhesion markers or markers of activation such as VLA-4 and LFA-1 on T cells were no different in treated versus control animals. Thus, anti-CD45RB can prevent EAE and appears to do so by altering T cell proliferation and cytokine production.
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PMID:Prevention of experimental allergic encephalomyelitis by an antibody to CD45RB. 987 18

Clinical trials that test the efficacy of Phlogenzym (consisting of the hydrolytic enzymes bromelain and trypsin and the anti-oxidant rutosid) as a treatment for T cell-mediated autoimmune diseases including multiple sclerosis (MS), type 1 diabetes and rheumatoid arthritis are presently ongoing. We tested the effects of Phlogenzym treatment in the murine model for MS, experimental allergic encephalomyelitis (EAE), a disease induced in SJL mice by immunization with proteolipid protein (PLP) peptide 139-151. Oral administration of Phlogenzym resulted in complete protection from EAE. In Phlogenzym-treated mice, the dose response curve of the PLP:139-151-specific T cell response was shifted to the right, that is, the primed T cells required higher peptide concentrations to become activated. Additionally, the T cell response to this peptide was shifted towards the T helper 2 cytokine profile. Both effects are consistent with an increased T cell activation threshold. In support of this interpretation, we found that the accessory molecules CD4, CD44, and B7-1 (all of which are involved in T cell co-stimulation) were cleaved by Phlogenzym, while CD3 and MHC class II molecules (which are involved in the recognition of antigens by T cells) and LFA-1 were unaffected. These data show the efficacy of oral Phlogenzym treatment in an animal model of T cell-mediated autoimmune disease and suggest that the protective effect might be the result of an increase in the activation threshold of the autoreactive T lymphocytes brought about by the cleavage of accessory molecules involved in the interaction of T cells and antigen presenting cells.
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PMID:Prevention of murine EAE by oral hydrolytic enzyme treatment. 1022 28

Additional structure-activity relationship studies on potent cyclic peptide inhibitors of very late antigen-4 (VLA-4) are reported. The new N- to C-terminal cyclic hexa-, hepta- and octapeptide inhibitors like cyclo(MeIle/MePhe-Leu-Asp-Val-X) (X = 2-4 amino acids containing hydrophobic and/or basic side chains) were synthesized using solid phase peptide synthesis methods. The peptides were evaluated in in vitro cell adhesion assays and in in vivo inflammation models. Many of the peptides like cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) (17), cyclo(MeIle-Leu-Asp-Val-D-Arg-D-Arg-D-Phe) (20), cyclo(MeIle-Leu-Asp-Val-D-Arg-D-Arg-MePhe) (21) and cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg-D-Ala-D-Ala) (23) were potent inhibitors of VLA-4-mediated cell adhesion and inhibited ovalbumin-induced delayed type hypersensitivity (DTH) response in mice. The more potent compounds were highly selective and did not affect U937 cell adhesion to fibronectin (VLA-5), phorbolmyristate acetate or PMA-differentiated U937 cell adhesion to intercellular cell adhesion molecule-1 (ICAM-1)-expressing Chinese hamster ovary cells (LFA-1) and adenosine diphosphate (ADP)-induced platelet aggregation (GPIIb/IIIa). In contrast to the inhibitors like Ac-cyclo(D-Lys-D-Ile-Leu-Asp-Val) and cyclo(CH2CO-Ile-Leu-Asp-Val-Pip-CH2CO-Ile-Leu-Asp-Val-Pip) described earlier, the new compounds were much more compatible with the depot formulations based on poly(DL-lactide-co-glycolide) polymers. The hexapeptide cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) (17) inhibited MOLT-4 cell adhesion to fibronectin and vascular cell adhesion molecule-1 (VCAM-1) with IC50 values of 260 and 330 nM, respectively, and did not show any significant effect against other integrins (IC50 > 300 microM). ZD7349 inhibited ovalbumin-induced DTH response in mice when administered continuously using a mini-pump (ED50 0.01 mg/kg/day) or when given as an s.c. or i.v. bolus injection at a dose of 1-10 mg/kg. ZD7349 was also active in type II collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) tests at a dose of 3-10 mg/kg. The peptide was released from some formulations over a period of 10-20 days. ZD7349 is currently undergoing pre-clinical investigation.
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PMID:Potent cyclic peptide inhibitors of VLA-4 (alpha4beta1 integrin)-mediated cell adhesion. Discovery of compounds like cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) compatible with depot formulation. 1096 69

Mononuclear cell infiltration into the CNS and induction of inflammatory cytokines and iNOS in diseases like multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE) have been implicated in subsequent disease pathogenesis and progression. We report that Lovastatin treatment blocks the clinical disease and induction of inflammatory cytokines and iNOS in spinal cords of MBP induced EAE rats. A significant number of the infiltrating cells in CNS were ED1+ cells of monocyte/macrophage lineage. To understand the mechanism of efficacy of Lovastatin against EAE, we examined the effect of Lovastatin on the transmigration of mononuclear cells into EAE spinal cord. The data presented here documents that Lovastatin treatment attenuates the transmigration of mononuclear cells possibly by down regulating the expression of LFA-1, a ligand for ICAM, in endothelial-leukocyte interaction. These results indicate that Lovastatin treatment prevents infiltration by mononuclear cells into the CNS of rats induced for EAE, thereby lessening the histological changes and clinical signs and thus ameliorating the disease. These observations indicate that Lovastatin treatment may be of therapeutic value against inflammatory disease process associated with infiltration of activated mononuclear cells into the tissue.
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PMID:Lovastatin treatment decreases mononuclear cell infiltration into the CNS of Lewis rats with experimental allergic encephalomyelitis. 1159 10

Lymphocyte recruitment into the brain is a critical event in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. We developed a novel intravital microscopy model to directly analyze through the skull the interactions between lymphocytes and the endothelium in cerebral venules of mice. No adhesive interactions were observed between lymphocytes and the nonactivated endothelium in the cerebral microcirculation. When brain venules were activated by pretreating mice with TNF-alpha or LPS, proteolipid protein 139-151 autoreactive T lymphocytes rolled and arrested; notably, only a few peripheral lymph node cells rolled and firmly adhered. Abs anti-P-selectin glycoprotein ligand-1 and anti-E- and P-selectin blocked tethering and rolling of autoreactive lymphocytes, suggesting that P-selectin glycoprotein ligand-1/endothelial selectins are critical in the recruitment of lymphocytes in inflamed brain venules. E- and P-selectin were expressed on cerebral vessels upon in vivo activation and had a patchy distribution during the preclinical phase of active and passive experimental autoimmune encephalomyelitis. LFA-1/ICAM-1 and alpha(4) integrins/VCAM-1 supported rolling, but were not relevant to rolling velocity. Firm arrest was mainly mediated by LFA-1 and ICAM-1. Pretreatment of autoreactive lymphocytes with pertussis toxin blocked integrin-dependent arrest, implicating a requirement for G(i) protein-dependent signaling in vessels from nonlymphoid districts. In conclusion, our data unveils the molecular mechanisms controlling the recruitment of autoreactive lymphocytes in inflamed cerebral vessels and suggest new insights into the pathogenesis of autoimmune inflammatory diseases of the CNS.
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PMID:Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric G(i)-linked receptors. 1182 30

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