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)

Previous studies have shown complex roles for the B7 receptors in providing both positive and negative regulation of experimental autoimmune encephalomyelitis (EAE). B7 blockade can ameliorate clinical EAE by indirectly interfering with CD28 signaling. However, B7 blockade can also result in disease exacerbation, presumably by interfering with regulatory B7:CTLA-4 interactions. Therefore, we have directly targeted T cell CD28 with specific mAbs both during initial Ag priming and after the onset of clinical signs of EAE. We found that CD28 blockade ameliorated EAE during the efferent and afferent limbs of the immune response. Disease amelioration at disease onset was associated with suppression of TNF-alpha production. Finally, Ab blockade of T cell CD28 during the first disease episode resulted in significant attenuation of the subsequent disease course, with no significant relapses. In contrast to previous studies targeting APC B7 with CTLA4-Ig, reagents targeting CD28 can block ongoing disease. Therefore, the present results suggest a clinically relevant therapeutic scenario for human diseases, such as multiple sclerosis.
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PMID:Blockade of CD28 during in vitro activation of encephalitogenic T cells or after disease onset ameliorates experimental autoimmune encephalomyelitis. 1041 78

T cell co-stimulation through the CD28 receptor on T cells is critical to the induction of experimental autoimmune encephalomyelitis (EAE). In this study, expression of the co-stimulatory ligands B7-1 (CD80) and B7-2 (CD86), as well as the receptors CD28 and CTLA-4, were quantitated in central nervous system (CNS) tissues from mice at various stages of EAE. Immunohistochemistry and flow cytometry of CNS-infiltrating cells revealed a high percentage of infiltrating T cells expressing B7-1 and B7-2 during acute, chronic and relapsing EAE. Of the infiltrating cells 10-20% were CTLA-4(+), most of which were CD4(+) T cells. B7-1 and B7-2 expression within the CNS during active EAE might increase the potential for local activation of autoimmune T cells; however, the high level of expression of B7 molecules may also provide a mechanism for the autoregulation of activated CTLA-4(+) T cells.
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PMID:T cells are the main cell type expressing B7-1 and B7-2 in the central nervous system during acute, relapsing and chronic experimental autoimmune encephalomyelitis. 1054 Mar 25

Recent evidence suggests that co-stimulation provided by B7 molecules through CTLA-4 is important in establishing peripheral tolerance. In the present study, we examined the kinetics of tolerance induction and T cell differentiation following i.p. administration of myelin basic protein (MBP) Ac1-11 in mice transgenic for a TCR V(beta)8.2 gene derived from an encephalitogenic T cell clone specific for MBP Ac1-11. Examination of the lymph node cell response after antigen administration demonstrated a dependence on CTLA-4 for i.p. tolerance induction. Examination of splenocyte responses suggested that i.p. antigen administration induced a T(h)2 response, which was potentiated by anti-CTLA-4 administration. Interestingly, i.p. tolerance was able to inhibit the induction of experimental autoimmune encephalomyelitis and anti-CTLA-4 administration did not alter this phenotype, suggesting that CTLA-4 blockade did not block tolerance induction. Thus, T cell differentiation and the dependence on CTLA-4 for tolerance induction following i.p. antigen administration differs between lymph node and spleen in a model of organ-specific autoimmunity.
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PMID:The role of CTLA-4 in tolerance induction and T cell differentiation in experimental autoimmune encephalomyelitis: i.p. antigen administration. 1059 Feb 53

Interactions between B7 molecules on antigen-presenting cells and CTLA-4 on T cells have been shown to be important in establishing tolerance. In the present study, we examined the kinetics of tolerance induction following i.v. administration of myelin basic protein (MBP) Ac1-11 in mice transgenic for a TCR V(beta)8.2 gene derived from an encephalitogenic T cell clone specific for MBP Ac1-11. Examination of the lymph node cell (LNC) response 10 days after antigen administration demonstrated an accentuation of i.v. tolerance induction with anti-CTLA-4 blockade. Anergy was induced in splenocytes by i.v. antigen administration as shown by a decrease in MBP-specific proliferation and IL-2 production, and anti-CTLA-4 potentiated this effect. In addition, i.v. antigen plus anti-CTLA-4 and complete Freund's adjuvant was not encephalitogenic. Interestingly, i.v. tolerance (a single injection) did not inhibit experimental autoimmune encephalomyelitis (EAE) and anti-CTLA-4 administration did not alter this phenotype. These results suggest that while the majority of MBP-specific T cells are tolerized by i.v. antigen and that this process is potentiated by anti-CTLA-4 administration, a population of T cells remains that is quite efficient in mediating EAE.
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PMID:The role of CTLA-4 in tolerance induction and ttigen administration cell differentiation in experimental autoimmune encephalomyelitis: i. v. antigen administration. 1059 Feb 54

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated, autoimmune disorder characterized by central nervous system (CNS) inflammation and demyelination, features reminiscent of the human disease, multiple sclerosis (MS). In addition to the signal the encephalitogenic T cell receives through the T cell receptor (TCR), a second signal, termed costimulation, is required for complete T cell activation. The B7 family of cell surface molecules expressed on antigen presenting cells (APC) is capable of providing this second signal to T cells via two receptors, CD28 and CTLA-4. Our studies have shown that costimulation provided by B7 molecules to its ligand CD28 is important in the initiation of the autoimmune response in EAE. Further, it appears the costimulation provided by B7-1 is important in disease development, while B7-2 may play an important regulatory role. We and others later showed that B7/CTLA-4 interaction plays a critical role in down-regulating the immune response. Previous work has shown that activated T cells and T cells of a memory phenotype are less dependent on costimulation than naive T cells. T cells reactive with myelin components that are involved in the pathogenesis of EAE and possibly MS would be expected to have been activated as part of the disease process. Building upon our prior work in the EAE model, we have tested the hypothesis that myelin-reactive T cells, which are relevant to the pathogenesis of CNS inflammatory demyelination, can be distinguished from naive myelin-reactive T cells by a lack of dependence upon costimulation for activation and that the costimulatory requirements of these myelin-reactive T cells change during the course of disease. Our studies in the EAE model have also addressed the mechanisms of extrathymic (peripheral) T cell tolerance following intravenous (i.v. ) administration of high dose antigen. It is believed that TCR signaling in the absence of costimulation is a vital component of peripheral tolerance mechanisms. However, recent evidence suggests that peripheral tolerance of antigen-specific T cells induced in vivo may require CTLA-4 engagement of the tolerized T cells. We have begun to examine the molecular mechanisms of tolerance induction following intravenous and intraperitoneal administration of myelin antigens in the EAE model and test the hypothesis that tolerance induction is dependent on the B7:CD28/CTLA-4 pathway. The results from our studies will enhance our understanding of the role that myelin-reactive T cells may play in the pathogenesis of MS. We have determined that MBP-reactive T cells in MS patients are less dependent upon CD28 costimulation than in normal controls, suggesting that these T cells were previously primed in vivo. Characterization of these CD28-independent myelin-specific T cells will have broad implications for a variety of immunologically based therapies in diseases such as MS.
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PMID:The role of costimulation in autoimmune demyelination. 1085 58

Theiler's murine encephalomyelitis virus (TMEV) is a natural mouse pathogen which causes a lifelong persistent infection of the central nervous system (CNS) accompanied by T-cell-mediated myelin destruction leading to chronic, progressive hind limb paralysis. TMEV-induced demyelinating disease (TMEV-IDD) is considered to be a highly relevant animal model for the human autoimmune disease multiple sclerosis (MS), which is thought to be initiated as a secondary consequence of a virus infection. Although TMEV-IDD is initiated by virus-specific CD4(+) T cells targeting CNS-persistent virus, CD4(+) T-cell responses against self myelin protein epitopes activated via epitope spreading contribute to chronic disease pathogenesis. We thus examined the ability of antibodies directed against B7 costimulatory molecules to regulate this chronic virus-induced immunopathologic process. Contrary to previous studies showing that blockade of B7-CD28 costimulatory interactions inhibit the initiation of experimental autoimmune encephalomyelitis, treatment of SJL mice at the time of TMEV infection with murine CTLA-4 immunoglobulin or a combination of anti-B7-1 and anti-B7-2 antibodies significantly enhanced clinical disease severity. Costimulatory blockade inhibited early TMEV-specific T-cell and antibody responses critical in clearing peripheral virus infection. The inhibition of virus-specific immune responses led to significantly increased CNS viral titers resulting in increased damage to myelin-producing oligodendrocytes. Following clearance of the costimulatory antagonists, epitope spreading to myelin epitopes was accelerated as a result of the increased availability of myelin epitopes leading to a more severe chronic disease course. Our results raise concern about the potential use of B7-CD28 costimulatory blockade to treat human autoimmune diseases potentially associated with acute or persistent virus infections.
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PMID:CD28 costimulatory blockade exacerbates disease severity and accelerates epitope spreading in a virus-induced autoimmune disease. 1095 34

During the progression of relapsing experimental autoimmune encephalomyelitis (R-EAE), in SJL mice, disease relapses are mediated by T cells specific for non-cross-reactive myelin epitopes, a process termed 'epitope spreading'. CTLA-4, a negative regulator of T cell function modulates R-EAE, in that CTLA-4 blockade exacerbates clinical R-EAE. Herein, we show that CTLA-4-mediated signaling negatively regulates the dynamic spread of autoreactive T cell responses during the course of autoimmune disease. Anti-CTLA-4 mAb, administration at various points during the progression of R-EAE exacerbated subsequent clinical disease and enhanced T cell reactivity to both inducing and relapse-associated epitopes. In addition, CTLA-4 blockade during acute disease inhibited clinical remission. Thus, CTLA-4-mediated events are critical for intrinsic regulation of epitope spreading during autoimmune disease.
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PMID:CTLA-4 downregulates epitope spreading and mediates remission in relapsing experimental autoimmune encephalomyelitis. 1099 19

Complete activation of T cells requires two signals: an Ag-specific signal delivered via the TCR by the peptide-MHC complex and a second costimulatory signal largely provided by B7:CD28/CTLA-4 interactions. Previous studies have shown that B7 blockade can either ameliorate experimental autoimmune encephalomyelitis by interfering with CD28 signaling or exacerbate the disease by concomitant blockade of CTLA-4 interaction. Therefore, we developed a functional CD28 mimic to selectively block B7:CD28 interactions. The design, synthesis, and structural and functional properties of the CD28 free peptide, the end group-blocked CD28 peptide, and its retro-inverso isomer are shown. The synthetic T cell-costimulatory receptor peptides fold into a polyproline type II helical structure commonly seen in regions of globular proteins involved in transient protein-protein interactions. The binding determinants of CD28 can be transferred onto a short peptide mimic of its ligand-binding region. The CD28 peptide mimics effectively block the expansion of encephalitogenic T cells in vitro suggesting the potential usefulness of the peptides for the treatment of autoimmune disease conditions requiring down-regulation of T cell responses.
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PMID:A retro-inverso peptide mimic of CD28 encompassing the MYPPPY motif adopts a polyproline type II helix and inhibits encephalitogenic T cells in vitro. 1141 97

Autoreactive T-cells are involved in demyelination, neurodegeneration, and the recruitment of peripheral macrophages and nonspecific activated T-cells in autoimmune diseases such as multiple sclerosis (MS). The ligation of costimulatory B7 molecules on microglia with CD28/CTLA-4 on T-cells is thought to be crucial to the onset and course of MS and its rodent model experimental autoimmune encephalomyelitis (EAE). It is currently unclear as to how far the nature of infiltrating T-cells has an impact on the expression of the B7 molecules on microglia, the resident antigen-presenting cells (APCs) of the brain. We studied the expression of B7-1 and B7-2 on microglia after encounter with preactivated Th1 and Th2 cells from transgenic mice whose T-cells express a receptor (TCR) either specific to myelin basic protein (MBP) or ovalbumin (OVA) using murine organotypic entorhinal-hippocampal slice cultures (OEHSC). Our main finding was that Th1 cells downregulate the constitutive expression of B7-2 and induce B7-1 expression while Th2 cells do not induce this B7-1 upregulation. The main difference between MBP- and OVA-specific cells was seen in experiments were Th1 cells had direct contact to APCs but not to brain tissue. In contrast to MBP-specific Th1 cells, OVA-specific Th1 cells required the addition of antigen to upregulate B7-1 and downregulate B7-2. When the cells were allowed to have contact to brain tissue, no difference was seen in the pattern of B7 regulation between OVA- and MBP-specific T-cells. Our data suggest that T-cells are able to modulate B7 expression on microglial cells in the brain independent of antigen presentation through TCR/MHC-II ligation but presumably by soluble mediators.
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PMID:Differential expression of costimulatory molecules B7-1 and B7-2 on microglial cells induced by Th1 and Th2 cells in organotypic brain tissue. 1174 77

The aim of this study was to identify immune-related genes affected by treatment with 17beta-estradiol (17beta-E2) that contribute to protection of T cell antigen receptor double transgenic mice from experimental autoimmune encephalomyelitis (EAE). The Affymetrix microarray system was used to screen more than 12,000 genes from E2-treated mice protected from EAE vs. control mice with severe EAE. In general, E2 treatment affected about 10% of the genes tested, but only 18 cytokine, chemokine/receptor, adhesion molecule, or activation genes were up- or down-regulated more than 2.4-fold by E2 treatment. Down-regulated genes included TNFalpha (an important proinflammatory cytokine in EAE); peptidoglycan recognition proteins (Pgrp); regulated on activation, normal T cell expressed and secreted (RANTES); and neural cell adhesion molecule (MCP-1). Up-regulated genes included cytotoxic T lymphocyte antigen-4 (CTLA-4; known to inhibit T cell activation), TGFbeta3, IL-18, and two interferon-gamma-induced genes, the chemokines: monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1beta (MIP-1beta), vascular cell adhesion molecule (VCAM), and disintegrin metalloprotease (thought to regulate TNFalpha production). These results implicate a limited set of known and previously unsuspected E2-sensitive genes that may be crucial for inhibition of EAE and potentially the human disease, multiple sclerosis.
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PMID:Evaluation of the effects of 17beta-estradiol (17beta-e2) on gene expression in experimental autoimmune encephalomyelitis using DNA microarray. 1175 23


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