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)

It has been shown that peripheral T cell tolerance can be induced by systemic antigen administration. We have been interested in using this phenomenon to develop antigen-specific immunotherapies for T cell-mediated autoimmune diseases. In patients with the demyelinating disease multiple sclerosis (MS), multiple potentially autoantigenic epitopes have been identified on the two major proteins of the myelin sheath, myelin basic protein (MBP) and proteolipid protein (PLP). To generate a tolerogenic protein for the therapy of patients with MS, we have produced a protein fusion between the 21.5-kD isoform of MBP (MBP21.5) and a genetically engineered form of PLP (deltaPLP4). In this report, we describe the effects of treatment with this agent (MP4) on clinical disease in a murine model of demyelinating disease, experimental autoimmune encephalomyelitis (EAE). Treatment of SJL/J mice with MP4 after induction of EAE either by active immunization or by adoptive transfer of activated T cells completely prevented subsequent clinical paralysis. Importantly, the administration of MP4 completely suppressed the development of EAE initiated by the cotransfer of both MBP- and PLP-activated T cells. Prevention of clinical disease after the intravenous injection of MP4 was paralleled by the formation of long-lived functional peptide-MHC complexes in vivo, as well as by a significant reduction in both MBP- and PLP-specific T cell proliferative responses. Mice treated with MP4 were resistant to disease when rechallenged with an encephalitogenic PLP peptide emulsified in CFA, indicating that MP4 administration had a prolonged effect in vivo. Administration of MP4 was also found to markedly ameliorate the course of established clinical disease. Finally, MP4 therapy was equally efficacious in mice defective in Fas expression. These results support the conclusion that MP4 protein is highly effective in suppressing disease caused by multiple neuroantigen epitopes in experimentally induced demyelinating disease.
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PMID:Treatment of experimental encephalomyelitis with a novel chimeric fusion protein of myelin basic protein and proteolipid protein. 883 9

Experimental autoimmune encephalomyelitis (EAE), a demyelinating disease of the central nervous system, is an animal model of paralyzing human disease, multiple sclerosis. EAE is readily induced by immunization with myelin basic protein (MBP) in mice transgenic for an alphabeta T cell receptor (TCR) that is specific for MBP. Subcutaneous injection of p17 (a peptide consisting of 17 NH2-terminal aminoacids of MBP) in complete Freund's adjuvant (CFA) causes paralysis. Induction of paralysis is inhibited by prior intraperitoneal injection of the same peptide in incomplete Freund's adjuvant (IFA). In addition, ongoing paralysis is ameliorated by subsequent intraperitoneal injection of p17 in IFA. Tolerance induction is equally efficient in Fas-deficient and IL-4-deficient TCR-transgenic mice, suggesting that neither activation-induced cell death nor differentiation into Th2 type cells plays a role in the tolerance induction. Tolerance induction by p17 seems to be based on reduction in the responsiveness of anti-MBP T cells, as documented by lower overall antigen-induced lymphokine production and proliferation, as well as diminished upregulation of early activation marker CD69 by tolerized T cells. We propose that continuous encounters of MBP-specific T cells with p17 play a critical role in the induction and maintenance of tolerance.
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PMID:Tolerance induction and autoimmune encephalomyelitis amelioration after administration of myelin basic protein-derived peptide. 925 49

Experimental autoimmune encephalomyelitis (EAE) is an organ-specific autoimmune disease inducible in susceptible animals by myelin Ag-specific CD4+ Th1 cells. The mechanisms by which these cells induce inflammation and demyelination in the central nervous system (CNS) are incompletely understood. To determine the roles of Fas and FasL in the involvement of CNS autoimmune injury, we determined susceptibility to EAE of Fas-or FasL-deficient mice. Compared with wild-type mice, mice expressing lpr (Fas) and gld (FasL) mutations were relatively resistant to the development of clinical EAE, and this correlated with fewer inflammatory infiltrates and cells undergoing apoptosis in the CNS of the mutant mice. The gld and lpr mice, however, developed significant T cell responses with production of Th1 cytokines in response to the encephalitogenic myelin peptide. These results suggest that the Fas/FasL pathway plays a critical role in the development of EAE probably by mediating apoptosis within the target tissue.
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PMID:Fas- and FasL-deficient mice are resistant to induction of autoimmune encephalomyelitis. 931 4

We have recently developed approaches for the generation of encephalitogenic T cell clones from mouse strains considered resistant to experimental allergic encephalomyelitis (EAE). By allowing for the direct use of knockout and mutant strains of mice, such clones allow for the efficient characterization of the relevance of specific gene products in the effector phase of EAE. Recent studies have suggested that Fas/FasL-mediated cell death may play a role in the pathogenesis of MS. To assess the role of Fas/FasL in EAE, we have tested the ability of wild-type C57BL/6-derived, encephalitogenic T cell clones to mediate adoptively transferred EAE in Fas-deficient C57BL/6-lpr mice. We now report that mice with the lpr mutation are fully susceptible to the adoptive transfer of EAE. Our results suggest that Fas/FasL-mediated cell death in the central nervous system does not play an integral role in the effector phase of acute EAE.
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PMID:Adoptively transferred EAE in mice bearing the lpr mutation. 940 Jun 31

The expression and action of Fas/Fas ligand (FasL) in multiple sclerosis has been postulated as a major pathway leading to inflammatory demyelination. To formally test this hypothesis, C57BL/6-lpr and -gld mice, which due to gene mutation express Fas and FasL in an inactive form, were immunized with myelin oligodendrocyte glycoprotein peptide(35-55). Whereas in wild-type C57BL/6 mice, experimental autoimmune encephalomyelitis (EAE), was chronic/relapsing, EAE in lpr and gld mice was characterized by a lower incidence of disease and a monophasic course. This contrasts with C57BL/6 perforin knockout mice, which showed the most severe form of EAE of all mouse strains tested, the course being chronic relapsing. The difference noted cannot be attributed to an involvement of FasL in oligodendrocyte damage since oligodendrocytes are insensitive to FasL-mediated cytotoxicity in vitro, and since in the acute phase of EAE gld mice also show CD4+ T cell infiltrates with associated demyelination in brain and spinal cord. Unlike oligodendrocytes, astrocytes were killed by FasL in vitro. It remains to be established whether this latter finding explains the different disease course of lpr and gld mice compared to wild-type and perforin knockout mice.
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PMID:Myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis is chronic/relapsing in perforin knockout mice, but monophasic in Fas- and Fas ligand-deficient lpr and gld mice. 946

The selective apoptotic elimination of autoreactive T cells in the central nervous system (CNS) contributes to the resolution of inflammation and the spontaneous clinical recovery from experimental autoimmune encephalomyelitis (EAE). To assess the molecular mechanisms involved in this process, we used three-colour flow cytometry to examine the expression of apoptosis-regulating proteins by inflammatory cells isolated from the spinal cords of Lewis rats immunized with myelin basic protein (MBP) and complete Freund's adjuvant. Throughout the course of the disease, which peaked 12-14 days after inoculation and was followed by clinical recovery, we analyzed the DNA content of the spinal cord inflammatory cells to assess apoptosis and, simultaneously, we measured the expression of five proteins (Fas, Fas ligand (Fas-L), Bcl-2, Bcl-x and Bax) which modulate the apoptotic process. Cells expressing the death effector molecules Fas and Fas-L were particularly prone to undergo apoptosis, and were over-represented in the apoptotic population. Of the cells expressing the cell death inhibitor Bcl-2, a low proportion were undergoing apoptosis compared to the proportion of the total inflammatory cell population undergoing apoptosis, indicating that expression of Bcl-2 protects against T cell apoptosis in this disease. There was no evidence, however, that the apoptotic regulators Bcl-x and Bax influenced the susceptibility to apoptosis. We also found that Vbeta8.2+ T cells, which constitute the predominant encephalitogenic MBP-reactive T cell population in the Lewis rat, have a high frequency of Fas and Fas-L expression compared to other inflammatory cells. This would account for the previously demonstrated susceptibility of Vbeta8.2+ T cells to apoptosis in the CNS in EAE. These findings support the hypothesis that autoreactive T cells are eliminated from the CNS during spontaneous recovery from EAE by activation-induced apoptosis involving the Fas pathway.
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PMID:The roles of Fas, Fas ligand and Bcl-2 in T cell apoptosis in the central nervous system in experimental autoimmune encephalomyelitis. 952 45

The Fas and FasL apoptotic pathway was investigated by protein immunohistochemistry, flow cytometry, and reverse transcriptase-PCR analysis to assess whether it is involved in the elimination of target and/or effector cells from the central nervous system (CNS) during adoptively transferred chronic relapsing experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. In addition to Fas and FasL, we studied Bax, an intracellular protein of the apoptotic cascade, the Bax antagonist and anti-apoptotic molecule Bcl-2, and DNA fragmentation, the final step in the apoptotic pathway. Infiltrating CD4+ T cells and parenchymal microglia expressed Fas, FasL, and Bax, and about half of these cells showed DNA fragmentation, a combination indicative of ongoing apoptosis. Using flow cytometry and reverse transcriptase-PCR, a positive correlation was seen between disease activity and up-regulation of the Fas system; in fact, Fas and FasL were expressed at low levels at the onset of EAE and increased at the height of disease to involve about one-third of all infiltrating lymphocytes. In the normal CNS, Fas immunoreactivity was constitutively present at low levels on oligodendrocytes and was up-regulated in the CNS during the course of EAE. However, oligodendrocytes showed no Bax reactivity or DNA fragmentation and expressed high levels of Bcl-2, as did the majority of infiltrating CD3+ cells, a pattern inconsistent with apoptosis. Thus, while molecules of the apoptotic cascade are well represented in the CNS during EAE, their expression correlates with elimination of infiltrating cells and microglia, not the myelinating cell, the oligodendrocyte.
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PMID:Cell death during autoimmune demyelination: effector but not target cells are eliminated by apoptosis. 954 18

Theiler's virus, a murine picornavirus, infects the central nervous systems of C57BL/6 mice and is cleared after approximately 10 days by a process which requires CD8+ cytotoxic T cells. We used perforin-deficient C57BL/6 mice to test the role of this protein in viral clearance. Perforin-deficient mice died from viral encephalomyelitis between days 12 and 18 postinoculation. They had high levels of viral RNA in their central nervous systems until the time of death. In contrast, viral RNA had disappeared by day 11 postinoculation in wild-type C57BL/6 mice. Cytotoxic T cells can kill infected cells by two main mechanisms: the secretion of the pore-forming protein perforin or the interaction of the Fas ligand with the apoptosis-inducing Fas molecule on the target cell. Our results demonstrate that clearance of Theiler's virus from the central nervous system in C57BL/6 mice is perforin dependent.
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PMID:Theiler's virus infection of perforin-deficient mice. 955 51

Apoptosis in T cells that have penetrated into the central nervous system (CNS) may be important for the physiological control of T cells with potentially dangerous reactivities to CNS antigens; such control may be dysfunctional in animals suffering from experimental autoimmune encephalomyelitis (EAE). In this study we examined the expression of Fas and FasL genes both in myelin basic protein (MBP)-reactive T cells and in glial cells and the susceptibility of these cells to death induced by Fas/FasL interaction. Both Fas and FasL gene expression is detectable in glial cells and MBP-reactive T cells. Cell death is not unidirectional: when T cells interact with glial cells death can be induced in the former or in the latter population. The ability to induce death of Fas-expressing cells varies greatly among different lines of MBP-reactive T cells, as does resistance to death induction by cells expressing FasL. Moreover, the ability of T cells both to deliver and to resist death signals is a function of their activation status: T cells freshly activated transmit a stronger apoptotic signal to Fas-positive target cells and are also more resistant to FasL-induced suicide. Soluble form of FasL provides a convenient titratable means of delivering death signals via Fas. However, comparison of the susceptibility of different targets to soluble FasL and to FasL expressed on the surface of a transfected glial line revealed differences, suggesting that signals arising from Fas/FasL interaction may be modulated by additional cell-surface molecules.
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PMID:Cell death mediated by Fas-FasL interaction between glial cells and MBP-reactive T cells. 958 91

The administration of soluble myelin proteins is an effective way of down-regulating the inflammation in the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. To shed more light on the mechanism of this antigen-specific therapy, we determined the effect of the intraperitoneal (i.p.) injection of soluble myelin basic protein (MBP) on Tcell apoptosis in the CNS and peripheral lymphoid organs of Lewis rats with EAE induced by inoculation with MBP and complete Freund's adjuvant. In particular we assessed the level of apoptosis of Vbeta8.2+ Tcells, which constitute the predominant encephalitogenic MBP-reactive T cell population in the Lewis rat. The daily i.p. injection of MBP for 3 days from the onset of neurological signs inhibited the further development of neurological signs of EAE. Using two-color flow cytometry we found that a single i.p. injection of MBP increased the level of apoptosis of the Vbeta8.2+ T cell population in the CNS to 26.2% compared to 7.4% in saline-treated rats and 7.6% in ovalbumin-treated rats. In contrast, treatment with MBP did not increase the level of apoptosis of the Vbeta8.2+ population in the popliteal lymph node draining the inoculation site (1.4%) or in the spleen (1.6%) above that occurring in saline-treated rats (1.6% and 1.1%, respectively). Limiting dilution analysis revealed that the frequency of T cells reactive to the major encephalitogenic epitope, MBP72-89, was decreased in the CNS but not in the popliteal lymph node by this treatment. Three-color flow cytometry in MBP-treated rats demonstrated that CNS Vbeta8.2+ T cells expressing Fas (CD95) and Fas ligand were highly vulnerable to apoptosis compared to Vbeta8.2+ Tcells not expressing these proteins. We conclude that the i.p. injection of MBP increases the spontaneously occurring Fas-mediated activation-induced apoptosis of autoreactive T cells in the CNS in EAE and that this contributes to the therapeutic effect of the injection.
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PMID:Soluble antigen therapy induces apoptosis of autoreactive T cells preferentially in the target organ rather than in the peripheral lymphoid organs. 960 69


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