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)

Theiler's murine encephalomyelitis virus (TMEV) persists in spinal cord white matter of susceptible mice (e.g., SJL/J), resulting in chronic inflammation and demyelination. Reconstitution of severe combined immunodeficient (SCID) mice with CD4(+) T- or CD8(+) T-lymphocytes results in extensive TMEV-induced demyelination, and depletion of CD8(+) T-lymphocytes in the early or late phase of the disease decreases the extent of demyelination, indicating that the cellular immune response against the virus plays a key role in myelin destruction. In susceptible mice, the demyelinated lesions are characterized by infiltration of a large numbers of B- and T-lymphocytes; whereas in mice resistant to TMEV-induced demyelination (e.g., C57BL/6), virus clearance requires infiltration of between 2.9 x 10(5) and 5.7 x 10(5) CD8(+) T-lymphocytes and between 3.4 x 10(5) and 6.1 x 10(5) CD4(+) T-lymphocytes per mouse in the brain 5-9 days post infection. Transgenic expression of capsid proteins of TMEV abrogates resistance in C56BL/6 mice, rendering the mice susceptible to TMEV persistence and demyelination. Comparison of the kinetics of virus replication and B- and T-lymphocyte infiltration in mice lacking key adhesion molecules (L-selectin (L-sel(-/-)), P-selectin (P-sel(-/-)), intracellular adhesion molecule-1 (ICAM-1(-/-)), or leukocyte function-associated antigen-1 (LFA-1(-/-))) demonstrates a role for individual adhesion molecules in recruitment of immune cells into central nervous system (CNS), but the role is not significant to prevent eventual virus clearance.
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PMID:The role of cellular immune response in Theiler's virus-induced central nervous system demyelination. 1474 31

Adhesion molecules are involved in the leukocyte recruitment of leukocytes at the blood-brain barrier. For this reason, it is important to understand how the regulation of their gene expression controls lymphocyte adhesion to endothelial cells in microvessels. Indeed, due to their specificity and diversity, adhesion molecules involved in extravasation play an essential role in the recruitment of activated leukocytes and activation of inflammation. Multiple sclerosis results from a chronic inflammation of the CNS which is mediated by infiltration of inflammatory cells from the immune system. Administration of glucocorticoids is a routine method to control multiple sclerosis since naturally derived or synthetic glucocorticoids are potent immunosuppressive and anti-inflammatory agents. Glucocorticoids also have beneficial effects in stabilizing the blood-brain barrier, as steroid hormones regulate the expression of adhesion molecule genes in endothelial cells. Other hormones such as estrogens modulate many endothelial cell biological activities, among them adhesion to leukocytes. They regulate expression of adhesion molecules genes on endothelial cells and are useful for the treatment of experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. The effects of glucocorticoids and estrogens on the expression of adhesion molecules on endothelial cells, including microvascular endothelial cells of the blood-brain barrier, are reviewed in this paper, as well as the involvement of these hormones in the therapy of experimental autoimmune encephalomyelitis and multiple sclerosis.
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PMID:Endothelial cells of the blood-brain barrier: a target for glucocorticoids and estrogens? 1476

VCAM-1 is an adhesion molecule that is important to leukocyte movement across the blood-brain barrier and is involved in the formation of destructive CNS inflammatory lesions in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). We examined VCAM-1 expression in the CNS of animals with passively induced EAE and found abundant expression not only on the CNS endothelium but also on astrocytes. We show that tumor necrosis factor receptor-1 (TNFR1) signaling is required for VCAM-1 expression by astrocytes, not the vascular endothelium. In addition, we demonstrate that VCAM-1 expression by astrocytes is crucial for T cell entry into the CNS parenchyma and is required for manifestation of neurological disease.
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PMID:TNFR1-dependent VCAM-1 expression by astrocytes exposes the CNS to destructive inflammation. 1514 10

Pleiotropic effects are now described for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (or statins) that might have utility in the context of chronic inflammatory autoimmune disease. Here we discuss the pharmacology and established uses of statins and in this context describe potential anti-inflammatory and immune-modulatory effects. An extensive in vitro data set defines roles for statins in modifying endothelial function, particularly with respect to adhesion molecule expression and apoptosis. Broader effects on leukocyte function have now emerged including altered adhesion molecule expression, cytokine and chemokine release and modulation of development of adaptive immune responses via altered MHC class II upregulation. In vivo data in several inflammatory models, including collagen-induced inflammatory arthritis and experimental autoimmune encephalomyelitis, suggest that such effects might have immune-modulatory potential. Finally, a recent clinical trial has demonstrated immunomodulatory effects for statins in patients with rheumatoid arthritis. Together with their known vasculoprotective effects, this growing body of evidence provides compelling support for longer-term trials of statin therapy in human disease such as rheumatoid arthritis.
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PMID:Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases? 1574 90

Soluble adhesion molecules are overexpressed in neuroinflammatory disorders. Their synthesis parallels that of their membrane-bound counterparts, which modulate lymphocyte transmigration through the blood-brain barrier. Blood-brain barrier cellular migration may be essential in the evolution of postinfectious inflammatory central nervous system disease. The serum levels of soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and soluble E-selectin were measured in 12 children with acute disseminated encephalomyelitis and in two control groups (35 healthy and 35 affected by noninflammatory neurologic diseases) of similar age. In patients with acute disseminated encephalomyelitis, soluble E-selectin serum levels were significantly higher (median 113 ng/mL, range 54-144) than in both control groups (median 44, range 31-63, and median 58, range 43-89, respectively; one-way analysis of variance, P < 0.0001); a statistical trend for higher levels of soluble intercellular adhesion molecule-1 was observed in acute disseminated encephalomyelitis subjects, whereas soluble vascular adhesion molecule-1 titers did not differ between the three groups. The specific role played by each of these molecules in lymphocyte extravasation and the differential cytokine modulation of their expression might explain the result. Further larger studies are required including serial measurements and cerebrospinal fluid analysis.
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PMID:Soluble adhesion molecules in acute disseminated encephalomyelitis. 1619 23

The infiltration of autoreactive T cells into the central nervous system (CNS) requires a complex molecular interplay between immune cells and the blood-brain barrier (BBB), especially involving adhesion molecules like intercellular adhesion molecule (ICAM)-1. Here we study the molecular expression at the BBB during adoptively transferred (AT) myelin basic protein (MBP)-experimental autoimmune encephalomyelitis (EAE) in vivo by sensitive particle acoustic quantification (SPAQ)-enhanced ultrasound after intravenous application of specific gas-filled MP (MP) targeted against ICAM-1 (ICAM-MP) as contrast agent. Our results reveal a clear periventricular and cerebellar upregulation of ICAM-1 expression at the disease maximum of AT-EAE. Moreover, SPAQ-enhanced ultrasound enables the sensitive quantification of ICAM-1 expression in vivo. This allows to monitor therapeutic changes as shown by suppression of ICAM-1 expression after pretreatment of rats with corticosteroids (P < 0.008). All imaging results were confirmed by parallel immunohistochemistry. In vivo magnetic resonance imaging and albumin staining of rat brains after sonification did not reveal a disturbance of the BBB, thereby proving the safety of the method. Subsequent application of specific MP did not influence follow-up measurements, a prerequisite for sequential measurements in longitudinal studies. Based on these data, quantitative molecular imaging of adhesion molecules by SPAQ-enhanced ultrasound proves to be a safe and reliable technology to monitor changes at the BBB in vivo.
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PMID:In vivo molecular imaging of adhesion molecules in experimental autoimmune encephalomyelitis (EAE). 1624 69

Multiple sclerosis (MS) has been recognised as a disease since the mid-19th century. The delineation of its CNS pathology, revealing the presence of inflammatory demyelination and relative sparing of axons, was originally interpreted as evidence of infection. Despite many studies, a primary infectious aetiology of MS has not been found. However, the occurrence of acute demyelinating disease following a variety of infections and vaccinations, leading to MS in about a third of cases, provides evidence for the existence of an auto-allergic pathogenesis for the disease. Improved understanding of the role of the blood-brain barrier in protecting the CNS, and the mechanisms by which cells gain entry into the brain and spinal cord has advanced the understanding of MS. Evidence of the central role of the adhesion molecule alpha4beta1-integrin (very late activation antigen-4 [VLA-4]) for lymphocytes in endothelial transmigration into the CNS specifically, has provided a major insight into the pathogenesis of human demyelinating disease and its experimental model, experimental autoimmune encephalomyelitis (EAE). This finding has led to a new window of therapeutic opportunity in MS. Monoclonal antibodies to VLA-4 abrogate the development of EAE in sensitised animals and may actually reverse its clinical and pathological findings in manifest disease. Natalizumab, one such monoclonal antibody, which is administered intravenously, has been found to be a promising agent in the treatment of MS. Although single doses produced no improvement in the speed or quality of recovery from acute exacerbations of MS in a phase II trial, long-term administration (in phase II and phase III trials) have produced significant benefits with results showing both a marked reduction in the risk of new magnetic resonance imaging lesions and a significant reduction in the risk of exacerbations within 2 months of the initiation of therapy. Phase III double-blinded controlled trials have provided additional evidence of safety and a favourable impact on exacerbation rates over the 1 year of administration. Unfortunately, the success of natalizumab has been curtailed by three cases of progressive multifocal leukoencephalopathy, which have prompted the manufacturer to voluntary withdraw the drug from the market. An independent review board is currently investigating the safety of the drug to determine whether it should return to the market. The demonstration that selective modulation (blocking) of the adhesion molecule VLA-4 by natalizumab in MS, resembling that observed in experimental disease, represents a major advance in rational therapy.
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PMID:The role of alpha-4 integrin in the aetiology of multiple sclerosis: current knowledge and therapeutic implications. 1626 63

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system. IL-12p40 monokines play a critical role in the generation of EAE-inducing CD4+T cells. Here we show that IL-12 directly upregulates the expression of the adhesion molecule, P-selectin glycoprotein ligand (PSGL-1), on B10.PL MBP-TCR transgenic T cells during their initial encounter with antigen. Pre-incubation of IL-12-stimulated myelin-reactive CD4+T cells with a blocking antibody against PSGL-1 reduced the incidence and severity of EAE. We conclude that IL-12-driven PSGL-1 expression can facilitate the development of autoimmune demyelination.
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PMID:IL-12 driven upregulation of P-selectin ligand on myelin-specific T cells is a critical step in an animal model of autoimmune demyelination. 1641 63

Multiple sclerosis (MS) is a devastating inflammatory disorder of the central nervous system (CNS). A major hallmark of MS is the infiltration of T cells reactive against myelin components. T cell infiltration is mediated by the interaction of integrins of the beta1 and beta2 family expressed by lymphocytes with their endothelial counter-receptors, vascular cell adhesion molecule 1 and intercellular adhesion molecule (ICAM)-1, respectively. We have reported previously that extracellular adherence protein (Eap) of Staphylococcus aureus exerts antiinflammatory activities by interacting with ICAM-1 and blocking beta2-integrin-dependent neutrophil recruitment. Here, we report that Eap inhibits experimental autoimmune encephalomyelitis (EAE) in mice. In vitro, Eap reduced adhesion of peripheral blood T cells to immobilized ICAM-1 as well as their adhesion and transmigration of TNF-activated human endothelium under static and shear flow conditions. These inhibitory effects were corroborated in two mouse models of inflammation. In a delayed-type hypersensitivity model, both T cell infiltration and the corresponding tissue edema were significantly reduced by Eap. In addition, Eap administration prevented the development of EAE and markedly decreased infiltration of inflammatory cells into the CNS. Strikingly, intervention with Eap after the onset of EAE suppressed the disease. Collectively, our findings indicate that Eap represents an attractive treatment for autoimmune neuroinflammatory disorders such as MS.
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PMID:Suppression of experimental autoimmune encephalomyelitis by extracellular adherence protein of Staphylococcus aureus. 1658 66

There has been a great deal of interest in adhesion molecules as targets for the treatment of multiple sclerosis and other inflammatory diseases. In this study, we systematically evaluate alpha(4) integrin and P-selectin as targets for therapy in murine models of multiple sclerosis-for the first time directly measuring the ability of their blockade to inhibit recruitment and relate this to clinical efficacy. Experimental autoimmune encephalomyelitis was induced in C57BL/6 or SJL/J mice and intravital microscopy was used to quantify leukocyte interactions within the CNS microvasculature. In both strains, pretreatment with blocking Abs to either alpha(4) integrin or P-selectin reduced firm adhesion to a similar extent, but did not block it completely. The combination of the Abs was more effective than either Ab alone, although the degree of improvement was more evident in SJL/J mice. Similarly, dual blockade was much more effective at preventing the subsequent accumulation of fluorescently labeled leukocytes in the tissue in both strains. Despite evidence of blockade of leukocyte recruitment mechanisms, no clinical benefit was observed with anti-adhesion molecule treatments or genetic deletion of P-selectin in the C57BL/6 model, or in a pertussis toxin-modified model in SJL/J mice. In contrast, Abs to alpha(4) integrin resulted in a significant delay in the onset of clinical signs of disease in the standard SJL/J model. Despite evidence of a similar ability to block firm adhesion, Abs to P-selectin had no effect. Importantly, combined blockade of both adhesion molecules resulted in significantly better clinical outcome than anti-alpha(4) integrin alone.
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PMID:Reevaluation of P-selectin and alpha 4 integrin as targets for the treatment of experimental autoimmune encephalomyelitis. 1667 Mar 33


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