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)

The costimulatory molecules CD80 and CD86 affect the differentiation of Th1 and Th2 subsets in experimental allergic encephalomyelitis, an autoimmune disorder. It is reported that the CD86 costimulator significantly affects disease outcome in Leishmania major infection, a classic model of Th subset polarization. Treatment of both L. major-resistant (C57BL/6) and susceptible (BALB/c) strains of mice with anti-CD86 substantially decreased parasite burden. This was accompanied, in BALB/c mice, by a decrease in Th2 cytokines. In contrast, anti-CD80 treatment did not affect parasite burden or cytokine levels in either strain. These data illustrate that in L. major infection, anti-CD86 can abrogate Th2 differentiation in a Th2-dominated susceptible mouse and can ameliorate disease in a Th1-dominated resistant strain, although the mechanism involved in the latter is not clear. It is concluded that in L. major infection, Th2 subset differentiation is critically dependent on interaction with the CD86 costimulatory molecule.
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PMID:Blockade of CD86 ameliorates Leishmania major infection by down-regulating the Th2 response. 894 Feb 22

B7/CD28-mediated costimulation is a promising target for therapeutic intervention in autoimmune diseases. However, studies addressing the differential functional roles of B7-1 and B7-2 in several autoimmune models have resulted in conflicting data, perhaps due to the temporal dynamics of B7-1 and B7-2 surface expression on different cell types and/or at different sites during an autoimmune response. We examined the temporal expression of B7 costimulatory molecules in the CNS and in various lymphoid organs during the course of murine relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE). Following immunization of SJL mice with the immunodominant proteolipid protein epitope, PLP139-151, surface expression of B7-1 was up-regulated on B cells, T cells, and macrophages, relative to B7-2, on CNS-infiltrating cells and on splenocytes. Similar enhancement in splenic B7-1 expression could be induced in SJL mice by the adoptive transfer of PLP139-151-specific cells or by immunization with CFA alone. These changes were not observed on lymph node cells, including those isolated from lymph nodes draining the immunization site, which maintained the predominant B7-2 expression pattern seen in naive mice. These phenotypic expression patterns correlated with the functional predominance of B7-1 in costimulating T cell activation when employing APCs from the spleen or CNS of mice with ongoing R-EAE, while B7-2 remained functionally predominant on lymph node APCs. Variation of phenotypic expression and functional dominance of costimulatory molecule expression in different lymphoid compartments during an active inflammatory autoimmune response has important implications in immune regulation, autoimmune pathogenesis, and therapeutic strategies.
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PMID:Tissue-specific up-regulation of B7-1 expression and function during the course of murine relapsing experimental autoimmune encephalomyelitis. 964 24

Multiple sclerosis (MS) is a severe central nervous system disease. Experimental autoimmune encephalomyelitis (EAE) mimics MS in mice. We report that spontaneous development of EAE in RAG-1-deficient mice transgenic for a myelin basic protein (MBP)-specific TCR (TgMBP+/RAG-1-/-) requires expression of the T cell costimulatory molecule CD28. Surprisingly, T cells from CD28-/-TgMBP+/RAG-1-/- mice proliferate and produce IL-2 in response to MBP1-17 peptide in vitro, excluding clonal anergy as the mechanism of CD28-regulated pathogenesis. Proliferation of autoaggressive T cells was dependent on the concentration of the MBP peptide, as was the development of MBP-induced EAE in CD28-deficient PL/J mice. These results provide the first genetic evidence that CD28 costimulation is crucial for MBP-specific T cell activation in vivo and the initiation of spontaneous EAE.
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PMID:CD28 costimulation is crucial for the development of spontaneous autoimmune encephalomyelitis. 1020 86

The T helper-1 (Th-1)/T helper-2 (Th-2) paradigm is relevant for the pathogenesis and therapy of multiple sclerosis. In experimental autoimmune encephalomyelitis, a shift towards a Th-2 immune response serves as treatment of the disease. In the human immune system, the factors which determine and modulate the differentiation of CD4+ T cells into the Th-1 or Th-2 phenotype have yet to be elucidated completely. Here, the split-well approach was used to analyse costimulatory requirements for the generation of myelin basic protein-specific T-cell subsets considered to play a major role in the pathogenesis of multiple sclerosis. Myelin basic protein-specific T-cell lines were isolated from peripheral blood cells of healthy individuals in the presence or absence of a blockade of the costimulatory molecule B7-1, previously reported to be involved in the development of Th-1 cells. T-helper type was determined by the interferon/interleukin ratio. Blockade of B7-1 did not increase the number of Th-2-like myelin basic protein-specific T-cell lines. Thus, these data show no evidence for an influence of B7-1 blockade on the development of human myelin basic protein-specific T-cell subsets. These results have to be taken into account when discussing whether antibody-mediated B7-1 blockade might be a suitable therapy in multiple sclerosis, as demonstrated in experimental autoimmune encephalomyelitis.
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PMID:No evidence for generation of Th-2-like MBP-specific T-cell lines by blockade of the costimulatory molecule B7-1. 1111 51

The inducible costimulatory molecule (ICOS) is expressed on activated T cells and participates in a variety of important immunoregulatory functions. After the induction of experimental allergic encephalomyelitis in SJL mice with proteolipid protein (PLP), brain ICOS mRNA and protein were up-regulated on infiltrating CD3+ T cells before disease onset. ICOS blockade during the efferent immune response (9-20 days after immunization) abrogated disease, but blockade during antigen priming (1-10 days after immunization) exacerbated disease. Upon culture with PLP and compared with immunized controls, splenocytes produced either decreased interferon-gamma (IFN-gamma, in efferent blockade) or excessive IFN-gamma (in priming blockade). PLP-specific immunoglobulin G1 was decreased in animals treated with anti-ICOS during antigen priming, but not in other groups.
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PMID:The costimulatory molecule ICOS plays an important role in the immunopathogenesis of EAE. 1142 35

CD100 belongs to the semaphorin family, several members of which are known to act as repulsive axonal guidance factors during neuronal development. We have previously demonstrated that CD100 plays a crucial role in humoral immunity. In this study, we show that CD100 is also important for cellular immunity through the maturation of dendritic cells (DCs). CD100(-/-) mice fail to develop experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein peptide, because myelin oligodendrocyte glycoprotein-specific T cells are not generated in the absence of CD100. In vitro studies with T cells from OVA-specific TCR-transgenic mice demonstrate that Ag-specific T cells lacking CD100 fail to differentiate into cells producing either IL-4 or IFN-gamma in the presence of APCs and OVA peptide. In addition, DCs from CD100(-/-) mice display poor allostimulatory capabilities and defects in costimulatory molecule expression and IL-12 production. The addition of exogenous soluble rCD100 restores normal functions in CD100(-/-) DCs and further enhances functions of normal DCs. Furthermore, treatment of Ag-pulsed DCs with both soluble CD100 and anti-CD40 before immunization significantly enhances their immunogenicity. This treatment elicits improved T cell priming in vivo, enhancing both primary and memory T cell responses. Collectively, these results demonstrate that CD100, which enhances the maturation of DCs, is essential in the activation and differentiation of Ag-specific T cells.
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PMID:Requirement for the lymphocyte semaphorin, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells. 1213 37

We investigated the in vivo function of the B7 family member B7-H3 (also known as B7RP-2) by gene targeting. B7-H3 inhibited T cell proliferation mediated by antibody to T cell receptor or allogeneic antigen-presenting cells. B7-H3-deficient mice developed more severe airway inflammation than did wild-type mice in conditions in which T helper cells differentiated toward type 1 (T(H)1) rather than type 2 (T(H)2). B7-H3 expression was consistently enhanced by interferon-gamma but suppressed by interleukin 4 in dendritic cells. B7-H3-deficient mice developed experimental autoimmune encephalomyelitis several days earlier than their wild-type littermates, and accumulated higher concentrations of autoantibodies to DNA. Thus, B7-H3 is a negative regulator that preferentially affects T(H)1 responses.
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PMID:The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. 1292 52

Axonal injury in the central nervous system (CNS) results in the degeneration of directly damaged fibers and also in the secondary degeneration of fibers that escaped the primary insult. Studies have shown that a protective T cell-mediated autoimmunity directed against myelin-related self-antigens is a physiological response to CNS insult, spontaneously elicited in strains that are constitutionally resistant to experimental autoimmune encephalomyelitis (EAE) but not in EAE-susceptible strains. The protective response following axonal injury can be induced in susceptible rats and boosted in resistant rats by passive or active immunization with myelin-related antigens. Here we show that oral administration of low-dose myelin basic protein (MBP) over a 5-day period is beneficial for post-traumatic survival of neurons in Lewis (EAE-susceptible) rats. Protection was accompanied by increased expression of the costimulatory molecule B7.2 in the traumatized nerves, similar to that seen after passive transfer of MBP-specific T cells. These results support the contention that properly controlled autoimmunity is the body's defense mechanism against non-infective insults. Oral immunization with MBP can be viewed as a way to control the autoimmunity capable of fighting off the consequences of CNS injury in EAE-susceptible strains.
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PMID:Beneficial effect of orally administered myelin basic protein in EAE-susceptible Lewis rats in a model of acute CNS degeneration. 1293 82

Upon peripheral immunization with myelin epitopes, susceptible rats and mice develop T cell-mediated demyelination similar to that observed in the human autoimmune disease multiple sclerosis (MS). In the same animals, brain injury does not induce autoimmune encephalomyelitis despite massive release of myelin antigens and early expansion of myelin specific T cells in local lymph nodes, indicating that the self-specific T cell clones are kept under control. Using entorhinal cortex lesion (ECL) to induce axonal degeneration in the hippocampus, we identified possible mechanisms of immune tolerance after brain trauma. Following ECL, astrocytes upregulate the death ligand CD95L, allowing apoptotic elimination of infiltrating activated T cells. Myelin-phagocytosing microglia express MHC-II and the costimulatory molecule CD86, but lack CD80, which is found only on activated antigen presenting cells (APCs). Restimulation of invading T cells by such immature APCs (e.g. CD80 negative microglia) may lead to T cell anergy and/or differentiation of regulatory/Th3-like cells due to insufficient costimulation and presence of high levels of TGF-beta and IL-10 in the CNS. Thus, T cell -apoptosis, -anergy, and -suppression apparently maintain immune tolerance after initial expansion of myelin-specific T lymphocytes following brain injury. This view is supported by a previous metastatistical analysis which rejected the hypothesis that brain trauma is causative of MS (Goddin et al., 1999). However, concomitant trauma-independent proinflammatory signals, e.g., those evoked by clinically quiescent infections, may trigger maturation of APCs, thus shifting a delicate balance from immune tolerance and protective immune responses to destructive autoimmunity.
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PMID:Self-tolerance in the immune privileged CNS: lessons from the entorhinal cortex lesion model. 1294 47

Dendritic cells (DC) are unique in their ability to prime naive T cells and initiate adaptive immunity. In recent years, DC were identified in the inflamed central nervous system (CNS), but their role in the initiation or regulation of the tissue specific immune response is unknown. As shown here, DC isolated from mice with experimental autoimmune encephalomyelitis (EAE) exhibit a maturational phenotype similar to immature bone marrow-derived DC or splenic DC as characterized by intermediate surface MHC class II and low expression of the costimulatory molecule CD80. However, they are unable to prime naive T cells. Moreover, they inhibit T cell proliferation stimulated by mature bone marrow-derived DC. TGFbeta, IL-10 and TRAIL were found to significantly contribute to the CNS-DC-mediated inhibition of allo-T cell proliferation. Thus CNS-DC may be the key responsibles for maintaining immune privilege within the inflamed CNS.
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PMID:The brain as an immune privileged site: dendritic cells of the central nervous system inhibit T cell activation. 1457 68


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