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)

Coronavirus infections of rodents can cause diseases of the central nervous system characterised by inflammatory demyelination. The lesions mimick in many aspects the pathology of multiple sclerosis in humans and of other neurological diseases. As an animal model for demyelination, we studied the MHV-JHM induced encephalomyelitis of Lewis rats. The pathomorphological analysis revealed patterns of lesions which developed in stages. Infected oligodendrocytes were first destroyed by necrosis. Later stages were characterized by demyelinated plaques. In the center of plaques, no virus antigen was found and oligodendrocytes were mainly destroyed by apoptosis. At the edge of plaques, virus antigen was expressed in parallel to infiltrations consisting of lymphocytes and macrophages. The prevailing mechanisms leading to demyelination may change individually and during defined stages of the disease. The transcriptional expression of chemoattractants and other mediators of inflammation was studied by semiquantitative RT-PCR. Virus induced inflammatory demyelination was accompanied by high expression of a relatively novel cytokine, the endothelial monocyte activating polypeptide II (EMAP II). By immunocytochemistry, EMAP II was detected in parenchymal microglia located both within the lesions and in unaffected areas. Furthermore, the level of transcriptional expression of the regulatory calcium binding S100 proteins MRP8, MRP14 and CP10 was associated with inflammatory demyelination and expression of IFN gamma, IL-2, TNF alpha, and iNOS.
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PMID:Coronavirus infection and demyelination. Development of inflammatory lesions in Lewis rats. 978 12

Autoimmune diseases in humans represent an immune attack on self tissue. Current therapies for almost all autoimmune diseases utilize potent and nonspecific immunosuppressive regimens. These therapies are complicated by their side effects and also place the patient at increased risk for opportunistic infections and malignancies. Our current understanding of immune mechanisms underlying autoimmune diseases remains limited. Ongoing studies include identifying genes that predispose an individual to developing autoimmunity, identification of autoantigens that trigger or perpetuate autoimmunity, and studies of immune cell interactions that lead to immune response. Although it may be many years before a full understanding of autoimmunity is obtained, treatment in animal models of autoimmune disease and some human clinical trials have begun to study alternative treatment approaches to therapy of autoimmune disease. Future therapies for autoimmune diseases should target the inappropriate autoimmune response. This article will describe the use of gene therapy in the treatment of autoimmune disease. We believe that autoimmunity can be ameliorated by delivering trans-acting immunoregulatory molecules by retrovirally transduced autoantigen specific T cells that home to lesions of autoimmunity. Until recently, there has not been a practical alternative to systemic delivery of immunoregulatory molecules, however systemic delivery suffers from toxic side effects and dangerous global immunosuppression. In order to study immune regulation using retroviral transduction for local delivery of immunoregulatory products, we used myelin basic protein (MBP) reactive T cell hybridomas in the murine model of multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE). In this report, we show that MBP reactive T cell hybridomas transduced to express IL-4 or TNF, ameliorated or exacerbated disease, respectively. Additionally, the effects of these cells were dependent on T cell receptor (TCR) expression, indicating that the effects were due to homing of the T cells and the local delivery of cytokines. We believe that gene therapy, allowing local delivery of immunoregulatory proteins by autoantigen specific T cells, represents an interesting potential therapy for autoimmune disease.
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PMID:Local delivery of cytokines by retrovirally transduced antigen-specific TCR+ hybridoma cells in experimental autoimmune encephalomyelitis. 983 Nov 93

Although autoreactive T cells recognizing self myelin Ags are present in most individuals, autoimmune disease of the central nervous system is a relatively rare medical condition. Development of autoimmune disease may require not only the presence of autoreactive T cells but also that autoreactive T cells become activated. Activation of T cells may require a minimum of two signals: an Ag-specific signal delivered by MHC-peptide complex and a second signal delivered by costimulatory molecules or cytokines. Although in vitro studies have suggested that cytokines, especially proinflammatory cytokines such as IL-1, IL-6, and TNF are involved in T cell activation, their precise roles in vivo are not clear. To determine the roles of proinflammatory cytokines in T cell activation in vivo and in the development of autoimmune disease, we have studied experimental autoimmune encephalomyelitis (EAE) in mice deficient in IL-6. We found that IL-6-deficient mice were completely resistant to EAE induced by myelin oligodendrocyte glycoprotein (MOG), whereas IL-6-competent control mice developed EAE characterized by focal inflammation and demyelination in the central nervous system and deficiency in neurologic functions. Furthermore, we established that the resistance to EAE in IL-6-deficient mice was associated with a deficiency of MOG-specific T cells to differentiate into either Th1 or Th2 type effector cells in vivo. These results strongly suggest that IL-6 plays a crucial role in the activation and differentiation of autoreactive T cells in vivo and that blocking IL-6 function can be an effective means to prevent EAE.
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PMID:IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. 986 71

Th1-polarized CD4+ T cells are considered central to the development of a number of target-directed autoimmune disorders including multiple sclerosis. The APC-derived cytokine IL-12 is a potent inducer of Th1 polarization in T cells. Inhibition of IL-12 in vivo blocks the development of experimental allergic encephalomyelitis, the animal model for multiple sclerosis. Based on previous work that suggests that the production of IL-12 by activated human central nervous system-derived microglia is regulated by autocrine TNF-alpha, we wanted to determine whether inhibition of TNF could induce a reduction of Th1 responses by its impact on systemic APCs. We found that soluble TNFR p75-IgG fusion protein (TNFR:Fc) inhibited production of IFN-gamma by allo-Ag-activated blood-derived human CD4 T cells. We documented reduced IL-12 p70 production by APCs in the MLR. By adding back recombinant IL-12, we could rescue IFN-gamma production, indicating that TNFR:Fc acts on APC-derived IL-12. Consistent with an inhibition of the Th1 polarization, we found a decreased expression of IL-12R-beta2 subunit on the T cells. Furthermore, the capacity of T cells to secrete IFN-gamma upon restimulation when previously treated with TNFR:Fc is impaired, whereas IL-2 secretion was not altered. Our results define a TNF-dependent cytokine network that favors development of Th1 immune responses.
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PMID:Inhibition of Th1 polarization by soluble TNF receptor is dependent on antigen-presenting cell-derived IL-12. 991 86

Migration of lymphocytes from the blood into the brain is a critical event in the pathogenesis of experimental autoimmune encephalomyelitis. Lymphocyte adhesion to brain endothelium is the first step in lymphocyte entry into the central nervous system, leading subsequently to myelin damage and paralysis. In this paper we show that the tyrosine kinase inhibitor, tyrphostin AG490, prevents binding of freshly isolated mouse lymph node cells and of in vivo activated lymphocytes to endothelium of inflamed brain in Stamper-Woodruff adhesion assays. Moreover, AG490 inhibits adhesion of encephalitogenic T cell lines to purified ICAM-1 and VCAM-1, molecules implicated in T cell recruitment into the central nervous system. In contrast, 2-h treatment of T cell lines with high doses of tyrphostin AG490 have no effect on the viability, intracellular calcium elevation induced by Con A or TCR cross-linking, proliferation, or TNF production by Ag-stimulated T cell lines. Systemic administration of AG490 prevents the accumulation of leukocytes in the brain and the development of experimental autoimmune encephalomyelitis induced by proteolipid protein, peptide 139-151-specific T cell lines in SJL/J mice. Blood leukocytes isolated from mice treated with tyrphostin AG490 are less adhesive on purified very late Ag-4 ligands compared with adhesion of leukocytes from control animals. Our results suggest that inhibition of signaling pathways involved in lymphocyte adhesion may represent a novel therapeutic approach for demyelinating diseases.
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PMID:Inhibition of experimental autoimmune encephalomyelitis by a tyrosine kinase inhibitor. 991 45

Experimental autoimmune encephalomyelitis (EAE) induction in TNF gene-targeted mice has resulted in conflicting reports in part due to the strong association of TNF with the MHC locus. To define the participation of TNF in EAE development, we back-crossed TNF-deficient mice (H-2b) into the SJL/J strain and directly compared them to H-2b congenic SJL or inbred SJL/J mice. Induction of EAE with myelin basic protein (MBP) revealed that H-2b congenic SJL mice are fully susceptible, indicating that the H-2b haplotype does not affect disease susceptibility. Using H-2b congenic SJL mice we show here that TNF deficiency modifies the normal course of EAE by considerably delaying the onset for approximately 5 days, suggesting that TNF is required for the normal initiation of MBP-induced EAE. However, TNF-deficient mice eventually developed severe EAE with perivascular inflammation and primary demyelination similar to wild-type controls, indicating that TNF is not essential during these processes. Taken together, these results indicate that although TNF is not required for the progression of MBP-induced EAE, it contributes positively by advancing the onset of disease.
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PMID:TNF accelerates the onset but does not alter the incidence and severity of myelin basic protein-induced experimental autoimmune encephalomyelitis. 1009 79

In a murine relapsing experimental allergic encephalomyelitis (EAE) model, gene therapy to block TNF was investigated with the use of a retroviral dimeric p75 TNF receptor (dTNFR) construct. To effectively produce these TNF inhibitors in vivo, a conditionally immortalized syngeneic fibroblast line was established, using a temperature-sensitive SV40 large T Ag-expressing retrovirus. These cells were subsequently infected with a retrovirus expressing soluble dTNFR. CNS-injected cells could be detected 3 mo after transplantation and were shown to produce the transgene product by immunocytochemistry and ELISA of tissue fluids. These levels of dTNFR protein were biologically active and could significantly ameliorate both acute and relapsing EAE. This cell-based gene-vector approach is ideal for delivering proteins to the CNS and has particular relevance to the control of inflammatory CNS disease.
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PMID:Gene therapy for chronic relapsing experimental allergic encephalomyelitis using cells expressing a novel soluble p75 dimeric TNF receptor. 1067 20

Experimental autoimmune encephalomyelitis develops in mice immunized with CNS antigens. To elucidate the role that specific proinflammatory cytokines play in the induction of this process we examined the development of EAE in mice with targeted disruptions of the TNF p55 or p75 or the IL-1 p80 receptors. EAE developed in mice with either one or both TNF receptors deleted although the onset of disease in mice with the p55 receptor deleted was delayed. However, mice with a deletion of the IL-1 p80 receptor failed to develop any inflammatory lesions in the CNS or evidence of clinical EAE. Thus we conclude that TNF or its receptors contribute to, but are not necessary for, the induction of EAE while the IL-1 p80 receptor is absolutely required. The p55 TNF receptor plays a role in determining the onset of disease and its severity.
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PMID:The induction of EAE is only partially dependent on TNF receptor signaling but requires the IL-1 type I receptor. 1077 5

The role of IL-12 in the evolution of immunoinflammatory responses at a localized tissue level was investigated. Transgenic mice were developed with expression of either both the IL-12 subunits (p35 and p40) or only the IL-12 p40 subunit genes targeted to astrocytes in the mouse CNS. Glial fibrillary acidic protein (GF)-IL-12 mice, bigenic for the p35 and p40 genes, developed neurologic disease which correlated with the levels and sites of transgene-encoded IL-12 expression. In these mice, the brain contained numerous perivascular and parenchymal inflammatory lesions consisting of predominantly CD4+ and CD8+ T cells as well as NK cells. The majority of the infiltrating T cells had an activated phenotype (CD44high, CD45Rblow, CD62Llow, CD69high, VLA-4 high, and CD25+). Functional activation of the cellular immune response was also evident with marked cerebral expression of the IFN-gamma, TNF, and IL-1alphabeta genes. Concomitant with leukocyte infiltration, the CNS expression of immune accessory molecules was induced or up-regulated, including ICAM-1, VCAM-1, and MHC class II and B7-2. Glial fibrillary acidic protein-p40 mice with expression of IL-12 p40 alone remained asymptomatic, with no inflammation evident at any age studied. The effect of local CNS production of IL-12 in the development of experimental autoimmune encephalomyelitis was studied. After immunization with myelin oligodendrocyte glycoprotein-peptides, GF-IL-12 mice had an earlier onset and higher incidence but not more severe disease. We conclude that localized expression of IL-12 by astrocytes can 1) promote the spontaneous development of activated type 1 T cell and NK cellular immunity and cytokine responses in the CNS, and 2) promote more effective Ag-specific T cell dynamics but not activity in experimental autoimmune encephalomyelitis.
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PMID:Astrocyte-targeted expression of IL-12 induces active cellular immune responses in the central nervous system and modulates experimental allergic encephalomyelitis. 1077 48

CD70/CD27 are cell surface molecules belonging to the TNF/TNF-receptor families. Ligation of CD27 by its ligand CD70 is thought to be important in T cell activation and T cell-B cell interaction. However, the in vivo function of these molecules during the establishment of cell-mediated immunity remains unclear. In this study, we examined the contribution of CD70-CD27 interactions to cell-mediated immunity by investigating the effect of anti-CD70 mAb on the development of experimental autoimmune encephalomyelitis (EAE). Treatment of SJL/J mice with anti-CD70 mAb prevented EAE induced by immunization with PLP(139-151). The preventive effect of anti-CD70 mAb was not due to the inhibition of T cell priming and antibody production from B cells, or immune deviation. However, TNF-alpha production was suppressed by treatment with anti-CD70 mAb, indicating that the ameliorating effect of anti-CD70 mAb appeared, at least in part, to be mediated by the inhibition of TNF-alpha production. These results indicate that the CD70-CD27 interaction plays a pivotal role in the development of cell-mediated autoimmune disease.
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PMID:Involvement of CD70-CD27 interactions in the induction of experimental autoimmune encephalomyelitis. 1099 21


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