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)

In vivo treatment of mice with the natural killer T (NKT) cell ligand, alpha-galactosylceramide (alphaGalCer), ameliorates autoimmune diabetes and experimental autoimmune encephalomyelitis (EAE) by shifting pathogenic Th1-type immune responses to nonpathogenic Th2-type responses. In the current study, in vivo activation of NKT cells in adult NZB/W mice by multiple injections of alphaGalCer induced an abnormal Th1-type immune response as compared with the Th2-type response observed in nonautoimmune C57BL/6 mice. This resulted in decreased serum levels of IgE, increased levels of IgG2a and IgG2a anti-double-stranded DNA (anti-dsDNA) Ab's, and exacerbated lupus. Conversely, treatment of NZB/W mice with blocking anti-CD1d mAb augmented Th2-type responses, increased serum levels of IgE, decreased levels of IgG2a and IgG2a anti-dsDNA Ab's, and ameliorated lupus. While total CD4+ T cells markedly augmented in vitro IgM anti-dsDNA Ab secretion by splenic B cells, the non-CD1d-reactive (CD1d-alphaGalCer tetramer-negative) CD4+ T cells (accounting for 95% of all CD4+ T cells) failed to augment Ab secretion. The CD1d-reactive tetramer-positive CD4+ T cells augmented anti-dsDNA Ab secretion about tenfold. In conclusion, activation of NKT cells augments Th1-type immune responses and autoantibody secretion that contribute to lupus development in adult NZB/W mice, and anti-CD1d mAb might be useful for treating lupus.
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PMID:Activation of natural killer T cells in NZB/W mice induces Th1-type immune responses exacerbating lupus. 1456 6

Class I and class II MHC-restricted T cells specific for proteins present in myelin have been shown to be involved in autoimmunity in the central nervous system (CNS). It is not yet known whether CD1d-restricted T cells reactive to myelin-derived lipids are present in the CNS and might be targeted to influence the course of autoimmune demyelination. Using specific glycolipid-CD1d tetramers and cloned T cells we have characterized a T cell population reactive to a myelin-derived glycolipid, sulfatide, presented by CD1d. This population is distinct from the invariant Valpha14+ NK T cells, and a panel of Valpha3/Valpha8+ CD1d-restricted NK T cell hybridomas is unable to recognize sulfatide in the presence of CD1d+ antigen-presenting cells. Interestingly, during experimental autoimmune encephalomyelitis a model for human multiple sclerosis, sulfatide-reactive T cells but not invariant NK T cells are increased severalfold in CNS tissue. Moreover, treatment of mice with sulfatide prevents antigen-induced experimental autoimmune encephalomyelitis in wild-type but not in CD1d-deficient mice. Disease prevention correlates with the ability of sulfatide to suppress both interferon-gamma and interleukin-4 production by pathogenic myelin oligodendrocyte glycoprotein-reactive T cells. Since recognition of sulfatide by CD1d-restricted T cells has now been shown both in mice and humans, study of murine myelin lipid-reactive T cells may form a basis for the development of intervention strategies in human autoimmune demyelinating diseases.
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PMID:Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide. 1505 63

Natural killer T (NKT) cells recognize glycolipid antigens presented by the MHC class I-related glycoprotein CD1d. The in vivo dynamics of the NKT cell population in response to glycolipid activation remain poorly understood. Here, we show that a single administration of the synthetic glycolipid alpha-galactosylceramide (alpha-GalCer) induces long-term NKT cell unresponsiveness in mice. NKT cells failed to proliferate and produce IFN-gamma upon alpha-GalCer restimulation but retained the capacity to produce IL-4. Consequently, we found that activation of anergic NKT cells with alpha-GalCer exacerbated, rather than prevented, B16 metastasis formation, but that these cells retained their capacity to protect mice against experimental autoimmune encephalomyelitis. NKT cell anergy was induced in a thymus-independent manner and maintained in an NKT cell-autonomous manner. The anergic state could be broken by IL-2 and by stimuli that bypass proximal TCR signaling events. Collectively, the kinetics of initial NKT cell activation, expansion, and induction of anergy in response to alpha-GalCer administration resemble the responses of conventional T cells to strong stimuli such as superantigens. Our findings have important implications for the development of NKT cell-based vaccines and immunotherapies.
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PMID:Glycolipid antigen induces long-term natural killer T cell anergy in mice. 1613 89

NKT cells emerge as important regulatory cells in autoimmune responses. Abnormalities in the numbers and functions of natural killer T (NKT) cells have been observed in patients with autoimmune diseases as well as in a variety of mouse strains that are genetically predisposed for development of autoimmune diseases. Unlike conventional T cells that recognize peptides in association with major histocompatibility complex (MHC), NKT cells recognize glycolipid antigens presented by the non-polymorphic MHC class I-like protein, CD1d. Recently, we and other groups have demonstrated that administration of glycolipid ligands such as alpha-galactosylceramide (alpha-GC ) or its sphingosine truncated derivative, OCH suppressed autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), diabetes in NOD mice and collagen-induced arthritis (CIA) by inducing T helper (Th) 2 bias of autoimmune T cells. OCH is a unique ligand to stimulate NKT cells to selectively produce Th2 cytokines whereas alpha-GC induces both interleukin (IL)-4 and interferon (IFN)-gamma, and is more beneficial for treatment of a wide variety of Th1-mediated autoimmune diseases. The lack of polymorphism of CD1d and cross-reactive responses of mouse and human NKT cells to the same ligand indicates that targeting NKT cells with this ligand may be an attractive means for intervening in human autoimmune diseases such as type I diabetes (T1D), multiple sclerosis (MS) and rheumatoid arthritis (RA). The present review will focus on the potential roles of NKT cells in the pathogenesis of autoimmune diseases and the recent advances in glycolipid therapy for autoimmune disease models. The molecular mechanism of OCH-induced Th2-selective cytokine secretion will also be discussed.
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PMID:Therapeutic potential of glycolipid ligands for natural killer (NK) T cells in the suppression of autoimmune diseases. 1617 91

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

Dendritic cells (DC) are key regulators of T cell immunity and tolerance. NKT cells are well-known enhancers of Th differentiation and regulatory T cell function. However, the nature of the DC directing T and NKT cell activation and polarization as well as the role of the respective CD1d Ags presented is still unclear. In this study, we show that peptide-specific CD4(+)IL-10(+) T cell-mediated full experimental autoimmune encephalomyelitis (EAE) protection by TNF-treated semimatured DCs was dependent on NKT cells recognizing an endogenous CD1d ligand. NKT cell activation by TNF-matured DCs induced high serum levels of IL-4 and IL-13 which are absent in NKT cell-deficient mice, whereas LPS plus anti-CD40-treated fully mature DCs induce serum IFN-gamma. In the absence of IL-4Ralpha chain signaling or NKT cells, no complete EAE protection was achieved by TNF-DCs, whereas transfer of NKT cells into Jalpha281(-/-) mice restored it. However, activation of NKT cells alone was not sufficient for EAE protection and early serum Th2 deviation. Simultaneous activation of NKT cells and CD4(+) T cells by the same DC was required for EAE protection. Blocking experiments demonstrated that NKT cells recognize an endogenous glycolipid presented on CD1d on the injected DC. Together, this indicates that concomitant and interdependent presentation of MHC II/self-peptide and CD1d/self-isoglobotrihexosylceramide to T and NKT cells by the same partially or fully matured DC determines protective and nonprotective immune responses in EAE.
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PMID:Interdependency of MHC class II/self-peptide and CD1d/self-glycolipid presentation by TNF-matured dendritic cells for protection from autoimmunity. 1740 72

Multiple sclerosis (MS) is a central nervous system (CNS) chronic inflammatory autoimmune disease with limited treatment modalities. Oral tolerance is one of the experimental methods that protects from autoimmune diseases. However, this method failed to be therapeutic in clinical trials. In our previous work we found that epicutaneous (EC) immunization with protein antigen induced a state of profound immunosuppression that inhibited inflammatory response in contact sensitivity, in experimental autoimmune encephalomyelitis (EAE) and in allogeneic skin graft rejection. In our current work, we precisely determined the phenotype of EC induced T suppressor (Ts) cells that reduce the progress of EAE. Employing TCRdelta-/-, CD1d-/- mice, we showed that EC induced Ts cells do not belong either to the population of TCRgammadelta cells or CD1d restricted NKT cells. Moreover, we noticed that a lack of CD1d-/- restricted NKT lymphocytes resulted in the induction of much stronger suppression of EAE than in wild type mice. This might suggest that NKT cells could interfere with the induction of Ts cells. Using beta2m-/- mice, negative selection and positive selection of EC induced Ts cells, we showed that Ts cells protecting from EAE belong to the population of TCRalphabeta+ CD4+ CD8+ double positive lymphocytes.
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PMID:Epicutaneous (EC) immunization with myelin basic protein (MBP) induces TCRalphabeta+ CD4+ CD8+ double positive suppressor cells that protect from experimental autoimmune encephalomyelitis (EAE). 1744 39

The invariant natural killer T cells (iNKT) cells have emerged as an important regulator of immunity to infection, cancer, and autoimmune diseases. They can be activated by glycolipids that bind to CD1d. The most effective iNKT ligand reported to date is alpha-galactosylceramide (alpha-GalCer), which stimulates iNKT cells to secrete both Th-1 and Th-2 cytokines. Indiscriminate induction of both types of cytokines could limit the therapeutic potential of iNKT ligands, as Th-1 and Th-2 cytokines play different roles under physiological and pathological conditions. Therefore, a ligand with a biased cytokine-release profile would be highly desirable. Here, we report the synthesis and biological activity of alpha-lactosylceramide (alpha-LacCer). Our data demonstrate that alpha-LacCer can stimulate iNKT cells to proliferate and release cytokines, both in vitro and in vivo. Interestingly, while alpha-LacCer is approximately 1000-times less efficient than alpha-GalCer in inducing Th-1 cytokines, it is as potent as alpha-GalCer in the induction of Th-2 cytokines; therefore, alpha-LacCer is a novel compound that induces a biased cytokine release. Processing by beta-glycosidase was critical for alpha-LacCer activity. Moreover, in vivo experiments suggest that alpha-LacCer is at least as potent as alpha-GalCer in the treatment of tumors and experimental autoimmune encephalomyelitis.
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PMID:Alpha-lactosylceramide as a novel "sugar-capped" CD1d ligand for natural killer T cells: biased cytokine profile and therapeutic activities. 1847 23

The GDVII strain of Theiler's murine encephalomyelitis virus (TMEV) causes an acute fatal polioencephalomyelitis in mice. Infection of susceptible mice with the DA strain of TMEV results in an acute polioencephalomyelitis followed by chronic immune-mediated demyelination with virus persistence in the central nervous system (CNS); DA virus infection is used as an animal model for multiple sclerosis. CD1d-restricted natural killer T (NKT) cells can contribute to viral clearance and regulation of autoimmune responses. To investigate the role of CD1d in TMEV infection, we first infected CD1d-deficient mice (CD1(-/-)) and wild-type BALB/c mice with GDVII virus. Wild-type mice were more resistant to virus than CD1(-/-) mice (50% lethal dose titers: wild-type mice, 10 PFU; CD1(-/-) mice, 1.6 PFU). Wild-type mice had fewer viral antigen-positive cells with greater inflammation in the CNS than CD1(-/-) mice. Second, an analysis of DA virus infection in CD1(-/-) mice was conducted. Although both wild-type and CD1(-/-) mice had similar clinical signs during the first 2 weeks after infection, CD1(-/-) mice had an increase in neurological deficits over those observed in wild-type mice at 3 to 5 weeks after infection. Although wild-type mice had no demyelination, 20 and 60% of CD1(-/-) mice developed demyelination at 3 and 5 weeks after infection, respectively. TMEV-specific lymphoproliferative responses, interleukin-4 (IL-4) production, and IL-4/gamma interferon ratios were higher in CD1(-/-) mice than in wild-type mice. Thus, CD1d-restricted NKT cells may play a protective role in TMEV-induced neurological disease by alteration of the cytokine profile and virus-specific immune responses.
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PMID:Regulatory role of CD1d in neurotropic virus infection. 1868 18

Invariant NKT cells are CD1d-restricted T cells specific for glycolipid Ags. Their activation or transgenic enrichment abrogates the development of experimental autoimmune encephalomyelitis (EAE). Herein, we demonstrate that in NKT-enriched mice the protection from EAE is associated with the infiltration of NKT cells in the CNS and the local expression of CD1d. This indicates that the CNS acquires the potential for local glycolipid presentation when exposed to inflammatory stress, permitting the triggering of NKT cells. To address the importance of CD1d-mediated Ag presentation, we used transgenic mice that express CD1d solely in the thymus. Interestingly, enrichment of NKT cells in these mice also conferred resistance to EAE, with an efficacy indistinguishable from that of NKT-enriched CD1d-sufficient mice. This protection was due to an abrogation of the encephalitogenic Th1 and Th17 response in the spleen, revealing that endogenous glycolipid presentation is dispensable for the regulatory function of NKT cells in EAE. Moreover, abrogating extrathymic CD1d expression failed to affect both the recruitment of NKT cells and their effector phenotype. CNS-infiltrating NKT cells were characterized by a cytotoxic IFN-gamma(high)IL-4(low)IL-10(low)granzyme B(high) profile, irrespective of the local expression of CD1d. Glycolipid Ag presentation is therefore dispensable for the control of autoimmune demyelination by NKT cells, underlining the importance of alternative cognate and/or soluble factors in the control of NKT cell function.
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PMID:Invariant NKT cells regulate experimental autoimmune encephalomyelitis and infiltrate the central nervous system in a CD1d-independent manner. 1868 21


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