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)

Autoimmune diseases result from a failure of tolerance. Although many self-reactive T cells are present in animals and humans, their activation appears to be prevented normally by regulatory T cells. In this study, we show that regulatory CD4(+) T cells do protect mice against the spontaneous occurrence of experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. Anti-myelin basic protein (MBP) TCR transgenic mice (T/R+) do not spontaneously develop EAE although many self-reactive T cells are present in their thymi and peripheral lymphoid organs. However, the disease develops in all crosses of T/R+ mice with recombination-activating gene (RAG)-1 knockout mice in which transgenic TCR-expressing cells are the only lymphocytes present (T/R- mice). In this study, crosses of T/R+ mice with mice deficient for B cells, CD8(+) T cells, NK1.1 CD4(+) T (NKT) cells, gamma/delta T cells, or alpha/beta T cells indicated that alpha/beta CD4(+) T cells were the only cell population capable of controlling the self-reactive T cells. To confirm the protective role of CD4(+) T cells, we performed adoptive transfer experiments. CD4(+) T cells purified from thymi or lymph nodes of normal mice prevented the occurrence of spontaneous EAE in T/R- mice. To achieve full protection, the cells had to be transferred before the recipient mice manifested any symptoms of the disease. Transfer of CD4(+) T cells after the appearance of symptoms of EAE had no protective effect. These results indicate that at least some CD4(+) T cells have a regulatory function that prevent the activation of self-reactive T cells.
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PMID:CD4(+) T cells prevent spontaneous experimental autoimmune encephalomyelitis in anti-myelin basic protein T cell receptor transgenic mice. 981 65

Although deficiencies in the NKT cell population have been observed in multiple sclerosis and mouse strains susceptible to experimental autoimmune encephalomyelitis (EAE), little is known about the function of these cells in CNS autoimmunity. In this work we report that TCR Valpha14-Jalpha281 transgenic nonobese diabetic mice, which are enriched in CD1d-restricted NKT cells, are protected from EAE. The protection is associated with a striking inhibition of Ag-specific IFN-gamma production in the spleen, implying modulation of the encephalitogenic Th1 response. This modulation is independent of IL-4 because IL-4-deficient Valpha14-Jalpha281 mice are still protected against EAE and independent of NKT cell-driven Th1 to Th2 deviation, because no increased autoantigen-specific Th2 response was observed in immunized Valpha14-Jalpha281 transgenic mice. Our findings indicate that enrichment and/or stimulation of CD1d-dependent NKT cells may be used as a novel strategy to treat CNS autoimmunity.
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PMID:Cutting edge: V alpha 14-J alpha 281 NKT cells naturally regulate experimental autoimmune encephalomyelitis in nonobese diabetic mice. 1205 8

NKT cells represent a unique T cell lineage that recognize glycolipid antigens in the context of the non-classical MHC class I molecule CD1d. NKT cells are potent producers of immunoregulatory cytokines, and have been implicated in several different autoimmune diseases in mice and humans, including Type 1 diabetes, experimental autoimmune encephalomyelitis--a mouse model for multiple sclerosis, systemic lupus erythematosus, and scleroderma. This review will cover the evidence for an involvement for NKT cells in these autoimmune diseases, and discuss the potential for therapeutic manipulation of these cells as a means of preventing autoimmune disease in the clinic.
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PMID:NKT cells: potential targets for autoimmune disease therapy? 1214 18

Recent works from our laboratory have demonstrated that natural killer (NK) cells and CD1d-restricted NKT cells are functionally biased toward producing type 2 cytokine in the remission phase of multiple sclerosis, an autoimmune disease putatively mediated by Th1 T cells. Indirect evidence would indicate that the type 2 bias of NK and NKT cells is not the cause of MS but an adaptive change to protect against activation of pathogenic Th1 cells. In fact, NK cells biased for producing IL-5 (NK2 cells) would inhibit induction of Th1 cells in vitro. Here I propose that it is a reasonable strategy for the control of MS to maximize and/or optimize the regulatory potentials of the innate regulatory cells. We have already found that experimental autoimmune encephalomyelitis (EAE), an animal model for MS, can be inhibited when NKT cells are partially stimulated by glycolipid ligands for NKT cells. Experiments proved that the suppression of disease is mediated by IL-4 produced by NKT cells. Future studies should be directed for identifying useful ligands for inducing regulatory cytokines from NK and NKT cells.
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PMID:[Therapeutic strategy for multiple sclerosis targeting NK and NKT cells]. 1223 27

Invariant NKT (inv. NKT) cells co-express an invariant alpha beta T cell receptor and the NK receptor NK1.1 and, upon CD1d-restricted recognition of the glycosphingolipid antigen alpha-galactosyl ceramide (alphaGalCer), secrete large amounts of regulatory cytokines. We investigated whether alphaGalCer-dependent activation of inv. NKT cells protects from experimental autoimmune encephalomyelitis (EAE), an immune-mediated disease of the central nervous system mimicking multiple sclerosis, induced in C57BL/6 mice by the myelin oligodendrocyte glycoprotein (MOG) encephalitogenic peptide aa 35-55. alphaGalCer was administered at the time of immunization s.c., mixed with complete Freund's adjuvant and MOG35-55 peptide, or administered i.p., diluted in PBS. EAE onset was delayed and disease severity was decreased only when alphaGalCer was s.c. administered. The protective effect of s.c. administration of alphaGalCer was associated with a markedly enhanced IFN-gamma production by liver-confined inv. NKT cells which, in turn, suppressed Th1-cytokine production and fostered secretion of IL-10 from MOG35-55-specific T cells. In vivo neutralization of IFN-gamma, but notIL-4, reversed the protective effect induced by s.c. administration of alphaGalCer, further confirming the critical regulatory role exerted by IFN-gamma-producing inv. NKT cells. Our results indicate that alphaGalCer, properly administered, may elicit an inv. NKT-cell-mediated suppressive effect on the effector function of encephalitogenic T cells; this effect is able to ameliorate autoimmunedemyelination.
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PMID:Activation of invariant NKT cells by alphaGalCer administration protects mice from MOG35-55-induced EAE: critical roles for administration route and IFN-gamma. 1281 43

We have previously demonstrated that NK cells and CD1d-restricted NKT cells regulate clinical and pathological manifestations of experimental autoimmune encephalomyelitis(EAE), an animal model for multiple sclerosis(MS). It is important to address whether NK and NKT cells are also involved in the pathogenesis of human MS. Our laboratory has recently showed that NK cells as well as CD4+ NKT cells are biased for secreting type 2 cytokines in the remission phase of MS. However, CD4- CD8- NKT cells, that mainly secrete TNF-alpha and IFN-gamma, are reduced in number and attenuated in cytokine secretion. These results support our postulate that NK and NKT cells are involved in the regulation of MS.
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PMID:[Involvement of NK and NKT cells in the pathogenesis of multiple sclerosis]. 1296 19

Experimental autoimmune encephalomyelitis(EAE), regarded as a model of multiple sclerosis, is a prototype Th1-mediated autoimmune disease. Although a prototype natural killer T(NKT) cell ligand, alpha-galactosylceramide(alpha-GC), would render NKT cells produce both IFN-gamma and IL-4, this novel ligand, an analog of alpha-GC with a truncated sphingosine chain, can induce a predominant production of IL-4. Consistently, an oral administration of this glycolipid induces Th2 bias of autoimmune T cells via production of IL-4 by NKT cells, leading to suppression of EAE. The lack of polymorphism of CD1d and cross-reactive response of mouse and human NKT cells to the same ligand would indicate that targeting NKT cells with this ligand may be an attractive means for intervening in multiple sclerosis.
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PMID:[Treatment for multiple sclerosis with a synthetic glycolipid]. 1296 36

Valpha14 NKT cells exhibit various immune regulatory properties in vivo, but their precise mechanisms remain to be solved. In this study, we demonstrate the mechanisms of generation of regulatory dendritic cells (DCs) by stimulation of Valpha14 NKT cells in vivo. After repeated injection of alpha-galactosylceramide (alpha-GalCer) into mice, splenic DCs acquired properties of regulatory DCs in IL-10-dependent fashion, such as nonmatured phenotypes and increased IL-10 but reduced IL-12 production. The unique cytokine profile in these DCs appears to be regulated by ERK1/2 and IkappaB(NS). These DCs also showed an ability to suppress the development of experimental allergic encephalomyelitis by generating IL-10-producing regulatory CD4 T cells in vivo. These findings contribute to explaining how Valpha14 NKT cells regulate the immune responses in vivo.
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PMID:Induction of regulatory properties in dendritic cells by Valpha14 NKT cells. 1614 9

Leukocyte trafficking to the central nervous system (CNS), regulated in part by chemokines, determines severity of the demyelinating diseases multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). To examine chemokine receptor CX3CR1 in EAE, we studied CX3CR1(GFP/GFP) mice, in which CX3CR1 targeting by insertion of Green Fluorescent Protein (GFP) allowed tracking of CX3CR1+ cells in CX3CR1(+/GFP) animals and cells destined to express CX3CR1 in CX3CR1(GFP/GFP) knockouts. NK cells were markedly reduced in the inflamed CNS of CX3CR1-deficient mice with EAE, whereas recruitment of T cells, NKT cells and monocyte/macrophages to the CNS during EAE did not require CX3CR1. Impaired recruitment of NK cells in CX3CR1(GFP/GFP) mice was associated with increased EAE-related mortality, nonremitting spastic paraplegia and hemorrhagic inflammatory lesions. The absence of CD1d did not affect the severity of EAE in CX3CR1(GFP/GFP) mice, arguing against a role for NKT cells. Accumulation of NK cells in livers of wild-type (WT) and CX3CR1(GFP/GFP) mice with cytomegalovirus hepatitis was equivalent, indicating that CX3CL1 mediated chemoattraction of NK cells was relatively specific for the CNS. These results are the first to define a chemokine that governs NK cell migration to the CNS, and the findings suggest novel therapeutic manipulation of CX3CR1+ NK cells.
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PMID:The neuronal chemokine CX3CL1/fractalkine selectively recruits NK cells that modify experimental autoimmune encephalomyelitis within the central nervous system. 1667 47

The therapeutic effect of monoclonal antibody (H57-597 MoAb) against T-cell receptor (TCR) alphabeta has been investigated on MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE), as a model system for T-cell-mediated chronic inflammation in the central nervous system (CNS). Short-term administration of the anti-TCR alphabeta immediately after immunization protected the mice from EAE. Furthermore, anti-TCR alphabeta treatment on an established disease restored the self-tolerance which led to a complete remission of EAE and a dramatic reduction of inflammatory cells in the CNS, while treatment with control antibody (hamster IgG) was ineffective. The remission was durable and not associated with disappearance of autoreactive T cells as measured by persistence of MOG-reactive T-cell proliferation in vitro. However, MOG-reactive T cells from anti-TCR-treated animals produced significantly lower amounts of inflammatory TNF-alpha and IFN-gamma. In addition, while a transient deletion of CD4(+) and CD8(+) T cells was observed, a population of T cells expressing CD3, NK1.1 and CD69 (NKT cells) were expanding. By transfer of spleen cells from anti-TCR MoAb-treated animals, we could show that the tolerogenic capacity can be transferred to untreated recipients with EAE. The data indicate therapeutic effect of anti-TCR alphabeta MoAb (H57-597), which represents a promising approach in treatment of T-cell-mediated autoimmune diseases.
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PMID:Monoclonal antibody against T-cell receptor alphabeta induces self-tolerance in chronic experimental autoimmune encephalomyelitis. 1721 65


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