Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reactive oxygen species (ROS) including nitric oxide (NO) are thought to be involved in inflammatory processes, exacerbating inflammation and tissue damage in multiple sclerosis (MS). The oil extracts of Nigella sativa (N. sativa) has been known as an antioxidant and antiinflammatory agent. The aim of the present study was to investigate the hypothesis that N. sativa components provide protection against oxidative stress induced by experimental autoimmune encephalomyelitis (EAE) in rats. For this purpose, EAE was induced in rats by using guinea pig myelin basic protein (MBP) in Freud's adjuvant with addition of heat-killed M. Tuberculosis H37Ra to test this hypothesis. In study groups, N. sativa was given by oral gavage to the rats. Treatment of the rats with N. sativa inhibited ROS production induced by EAE showing diminished levels of MDA of both brain and medulla spinalis tissues. Although there was a significant decrease in brain NO level, there was an increase in medulla spinalis NO level after EAE induction in rats. N. sativa regulated tissue NO levels in some extend when applied together with EAE. When N. sativa was given alone to the rats, no changes were shown in brain, medulla spinalis, and serum oxidant/antioxidant parameters. In conclusion, N sativa may protect brain and medulla spinalis tissues against oxidative stress induced by EAE. In addition, N. sativa display its antioxidant and regulatory effects via inflammatory cells rather than the host tissue (brain and medulla spinalis) for EAE in rats.
Cell Mol Biol (Noisy-le-grand) 2005 Sep 05
PMID:The effect of Nigella sativa oil against experimental allergic encephalomyelitis via nitric oxide and other oxidative stress parameters. 1619 2

Hematopoietic stem cell (HSC) transplantation is a potential therapy that can offer multiple sclerosis patients a radical, potentially curative treatment. Using experimental autoimmune encephalomyelitis (EAE) as a model, we previously reported that retrovirally transduced B cells expressing myelin basic protein (MBP), MBP Ac1-11, or myelin oligodendrocyte glycoprotein p35-55 induced tolerance and reduced symptoms. Here, we extend our tolerance approach using bone marrow (BM) cells expressing full-length phospholipid protein (PLP) in a model for relapsing, remitting EAE. Using GFP expression as a marker, we found that up to 50% of cells were positive for transgene expression in peripheral blood after 900 rad irradiation and transduced BM transplantation, and expression was stable in hematopoietic lineages for over 10 weeks. Upon challenge, T cell proliferation in response to PLP p139-151 was reduced and EAE was completely abolished in a pretreatment protocol. In addition, protection from EAE could be achieved with PLP-transduced BM cells given on day 12 after immunization, a potential therapeutic protocol. Finally, the protective effect of PLP-expressing BM could also be observed using a nonmyeloablative protocol, albeit with lower efficacy. Our results suggest that HSC may be useful to achieve long-lasting tolerance to protect mice from EAE and possibly to promote CNS repair in ongoing EAE.
Mol Ther 2006 Jan
PMID:Bone marrow transplantation combined with gene therapy to induce antigen-specific tolerance and ameliorate EAE. 1621 91

Experimental autoimmune encephalomyelitis (EAE) is a good model for human multiple sclerosis (MS) research. However, there are some defects in the traditional models. Here, we improved the model by using the human myelin basic protein (MBP) as antigen. EAE was induced by immunization of female Wistar rats with human MBP. Compared with the traditional models, the new model was evaluated by clinical signs to pathological changes. The immune state of the model was assessed by the lymphocyte infiltrative response and levels of TNF-alpha, IFN-gamma, IL-10. It was found that most of rats exhibited tail tone loss and hind-limb paralysis, also there were demyelination, infiltrative lymphocyte foci, "neuronophagia" in the cortex of cerebra and the white matter of spinal cords. PBMCs and spleen lymphocytes were strongly responsive to the stimulation of MBP and PHA. The levels of TNF-alpha and IFN-gamma were altered with the severity of EAE. In the remitting phase, IL-10 was increased significantly. This study demonstrates that the animal model of EAE induced by human MBP bears resemblance to the features of human multiple sclerosis and promises to be a better model than ever before for the study of MS.
Cell Mol Immunol 2004 Oct
PMID:Evaluation of a rat model of experimental autoimmune encephalomyelitis with human MBP as antigen. 1628

[Arg(91), Ala(96)] MBP(87-99) is an altered peptide ligand (APL) of myelin basic protein (MBP), shown to actively inhibit experimental autoimmune encephalomyelitis (EAE), which is studied as a model of multiple sclerosis (MS). The APL has been rationally designed by substituting two of the critical residues for recognition by the T-cell receptor. A conformational analysis of the APL has been sought using a combination of 2D NOESY nuclear magnetic resonance (NMR) experiments and detailed molecular dynamics (MD) calculations, in order to comprehend the stereoelectronic requirements for antagonistic activity, and to propose a putative bioactive conformation based on spatial proximities of the native peptide in the crystal structure. The proposed structure presents backbone similarity with the native peptide especially at the N-terminus, which is important for major histocompatibility complex (MHC) binding. Primary (Val(87), Phe(90)) and secondary (Asn(92), Ile(93), Thr(95)) MHC anchors occupy the same region in space, whereas T-cell receptor (TCR) contacts (His(88), Phe(89)) have different orientation between the two structures. A possible explanation, thus, of the antagonistic activity of the APL is that it binds to MHC, preventing the binding of myelin epitopes, but it fails to activate the TCR and hence to trigger the immunologic response. NMR experiments coupled with theoretical calculations are found to be in agreement with X-ray crystallography data and open an avenue for the design and synthesis of novel peptide restricted analogues as well as peptide mimetics that rises as an ultimate goal.
J Mol Graph Model 2006 Sep
PMID:A putative bioactive conformation for the altered peptide ligand of myelin basic protein and inhibitor of experimental autoimmune encephalomyelitis [Arg91, Ala96] MBP87-99. 1631 Mar 86

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.
Cell Mol Immunol 2005 Dec
PMID:FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. 1642 94

A growing body of evidence suggests that axonal loss and neurodegeneration are responsible for the permanent neurological deficit that typically develops in the course of MS. To investigate the neurodegenerative component of MS pathogenesis, we examined the expression of alpha-synuclein, a protein whose accumulation is common to many neurodegenerative disorders, under conditions of immune-mediated inflammatory demyelination. alpha-Synuclein expression was examined in the spinal cord of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats using immunofluorescence and in situ hybridization and in postmortem tissues from cases of secondary progressive MS using immunohistochemistry. alpha-Synuclein upregulation was detected in neurons and glia in and close by lesions and in normal appearing spinal cord EAE tissue at the protein and mRNA levels. alpha-Synuclein positive neurons and glia appeared early, and their number was maximal during EAE exacerbations, but some expression was maintained throughout the course of EAE. In addition, increased alpha-synuclein expression was detected in neurons and glia in and close to MS lesions. Although the increased expression of alpha-synuclein was detected as a granular cytoplasmic labeling rather than inclusion bodies, this result does suggest that neuronal cell death in immune-mediated demyelinating disease may share some common features with other neurodegenerative conditions.
Mol Cell Neurosci 2006 Apr
PMID:Upregulation of alpha-synuclein in neurons and glia in inflammatory demyelinating disease. 1650 61

The transmembrane adaptor molecule TRIM is strongly expressed within thymus and in peripheral CD4(+) T cells. Previous studies suggested that TRIM is an integral component of the T-cell receptor (TCR)/CD3 complex and might be involved in regulating TCR cycling. To elucidate the in vivo function of TRIM, we generated TRIM-deficient mice by homologous recombination. TRIM(-/-) mice develop normally and are healthy and fertile. However, the animals show a mild reduction in body weight that appears to be due to a decrease in the size and/or cellularity of many organs. The morphology and anatomy of nonlymphoid as well as primary and secondary lymphoid organs is normal. The frequency of thymocyte and peripheral T-cell subsets does not differ from control littermates. In addition, a detailed analysis of lymphocyte development revealed that TRIM is not required for either positive or negative selection. Although TRIM(-/-) CD4(+) T cells showed an augmented phosphorylation of the serine/threonine kinase Akt, the in vitro characterization of peripheral T cells indicated that proliferation, survival, activation-induced cell death, migration, adhesion, TCR internalization and recycling, TCR-mediated calcium fluxes, tyrosine phosphorylation, and mitogen-activated protein family kinase activation are not affected in the absence of TRIM. Similarly, the in vivo immune response to T-dependent and T-independent antigens as well as the clinical course of experimental autoimmune encephalomyelitis, a complex Th1-mediated autoimmune model, is comparable to that of wild-type animals. Collectively, these results demonstrate that TRIM is dispensable for T-cell development and peripheral immune functions. The lack of an evident phenotype could indicate that TRIM shares redundant functions with other transmembrane adaptors involved in regulating the immune response.
Mol Cell Biol 2006 May
PMID:Normal T-cell development and immune functions in TRIM-deficient mice. 1661 2

The central nervous system (CNS) is traditionally viewed as an immune privileged site in which overzealous immune cells are prevented from doing irreparable damage. It was believed that immune responses occurring within the CNS could potentially do more damage than the initial pathogenic insult itself. However, virtually every aspect of CNS tissue damage, including degeneration, tumors, infection, and of course autoimmunity, involves a significant cellular inflammatory component. While the blood-brain barrier (BBB) inhibits diffusion of hydrophilic (immune) molecules across brain capillaries, activated lymphocytes readily pass the endothelial layer of postcapillary venules without difficulty. In classic neuro-immune diseases such as multiple sclerosis or acute disseminated encephalomyelitis, it is thought that neuroantigen-reactive lymphocytes, which have escaped immune tolerance, now invade the CNS and are responsible for tissue damage, demyelination, and axonal degeneration. The developed animal model for these disorders, experimental autoimmune encephalomyelitis (EAE), reflects many aspects of the human conditions. Studies in EAE proved that auto-reactive encephalitogenic T helper (Th) cells are responsible for the onset of the disease. Th cells recognize their cognate antigen (Ag) only when presented by professional Ag-presenting cells in the context of major histocompatibility complex class II molecules. The apparent target structures of EAE immunity are myelinating oligodendrocytes, which are not capable of presenting Ag to invading encephalitogenic T cells. A compulsory third party is thus required to mediate between the attacking T cells and the myelin-expressing target. This review will discuss the recent advances in this field of research and we will discuss the journey of an auto-reactive T cell from its site of activation into perivascular spaces and further into the target tissue.
J Mol Med (Berl) 2006 Jul
PMID:Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain. 1677 56

In contrast to serial injections of recombinant interferon-beta (IFN-beta) for long-term therapy of multiple sclerosis (MS), prolonged systemic delivery of proteins derived through in vivo gene transfer may provide a more clinically relevant alternative. Here we compare the therapeutic efficacies of electroporation (EP)-mediated intramuscular IFN-beta gene transfer with repeated alternate-day injections of recombinant IFN-beta after the onset of relapsing-remitting experimental autoimmune encephalomyelitis (EAE), an animal model widely used in MS research. We show for the first time that a single EP-mediated intramuscular administration of 20 microg of an IFN-beta-expressing plasmid provides long-term expression of interferon-inducible genes and is therapeutic in ongoing established EAE. The achieved therapeutic effects of IFN-beta gene delivery were comparable to an 8-week regimen of 10,000 IU rIFN-beta injected every other day and involved a significant inhibition of disease progression and a significant reduction of EAE relapses compared to untreated or null-vector-treated mice. Our results indicate the viability of a convenient and effective gene-based alternative for long-term IFN-beta protein therapy in MS.
Mol Ther 2006 Sep
PMID:Gene-based intramuscular interferon-beta therapy for experimental autoimmune encephalomyelitis. 1678 9

T-lymphocytes are essential participants of adaptive immunity, essential for cellular and humoral recognition of foreign antigens. In pathogenic situations T cells may, however, also recognize self-antigens, causing detrimental autoimmune responses that ultimately lead to autoimmune disease. Experimental autoimmune encephalomyelitis (EAE) is a murine model for the autoimmune disease multiple sclerosis, in which T cells invade the central nervous system and destroy the myelin sheath around neuronal axon fibers. In some EAE systems, the sequence of the alpha- or beta-chains of the pathogenic T-cell receptor is known and makes it possible to induce an immune response that eliminates these self-specific T cells. Herein we describe a method, using DNA vaccination that allows induction of such an immune response to protect mice from the development of EAE.
Methods Mol Med 2006
PMID:Protection from autoimmunity by DNA vaccination against T-cell receptor. 1698 60


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