Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoimmune disorders represent inappropriate immune responses directed at self-tissue. Because CD4+ T cells are important mediators in the pathogenesis of autoimmune disease, they are ideal candidates for cell-based gene therapy. Using retrovirally-transduced cells and luciferase bioluminescence, we have demonstrated that primary T cells and hybridomas, rapidly and preferentially home to the sites of inflammation in organ-specific autoimmune disease. These cells, transduced with retroviral vectors to drive expression of various 'regulatory proteins', such as IL-4, IL-10 and IL-12p40, deliver these immunoregulatory proteins to the inflamed lesions, providing therapy for experimental models of autoimmune disease such as EAE, CIA and NOD mice. This technique was originally developed in our lab in the murine model of multiple sclerosis, EAE, where T cell hybridomas reactive with myelin basic protein (MBP) were transduced to express and used to deliver the modulatory cytokine, IL-4. Recently we have observed that the cytokine receptor antagonist, IL-12p40 transduced anti-myelin basic protein (MBP) TCR-transgenic T cells (but not CII-reactive T cells) were effective in preventing EAE whereas the CII-reactive, but not MBP-reactive T cells, transduced to express IL-12p40, would treat CIA.
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PMID:Adoptive cellular gene therapy of autoimmune disease. 1284 98

Peptide-mediated immunotherapy has been studied in a number of experimental models of autoimmune diseases and has also been tested in human patients to a certain extent. Copolymer 1 is a synthetic amino acid copolymer that has been demonstrated to suppress experimental autoimmune encephalomyelitis (a model for multiple sclerosis) when administered parenterally. Some study results indicate that mucosal tolerance induced by appropriate recombinant peptide fragments of human AChR is effective in suppressing experimental autoimmune myasthenia gravis and might be considered as a therapeutic modality for patients with MG. A peptide of the heat-shock protein 60 molecule, designated peptide p277, was shown to be a target of T cells in autoimmune diabetes in NOD mice, and intraperitoneal injections of glutamic acid decarboxylase (GAD) peptide 524-543 delayed the onset of diabetes and significantly reduced its incidence. Experimental evidence has revealed that CDR-based peptides may be potential candidates for the therapy of systemic lupus erythematosus. The use of synthetic peptides that focus on neutralization of pathogenic anti-beta 2GPI antibodies represents a possible new therapeutic approach to antiphospholipid syndrome. Studies in both acute and chronic-relapsing experimental autoimmune uveoretinitis have indicated that oral administration of S-Ag, S-Ag-derived peptides, inter-photoreceptor retinoid binding protein or HLA-derived peptides before immunization can protect animals from the disease.
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PMID:Peptide immunotherapy in autoimmune diseases. 1293 33

The skin is both an essential barrier for host defense and an important organ of immunity. In this study, we show that the application of cholera toxin to intact mouse skin induces and enhances autoimmune diseases affecting organs at distant anatomic sites, whereas its administration by the mucosal route has been reported to have the opposite effect. First, the CNS autoantigen myelin oligodendrocyte glycoprotein 35-55, when applied repeatedly with cholera toxin to the intact skin of healthy C57BL/6 mice, induced relapsing paralysis with demyelinating immunopathologic features similar to multiple sclerosis. Second, the application of cholera toxin in the absence of autoantigen exacerbated the severity of conventional experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein in CFA. Third, the application of cholera toxin to the intact skin of NOD/Lt mice, with or without insulin B peptide 9-23, exacerbated insulitis and T lymphocyte-derived IFN-gamma and IL-4 production in the islets of Langerhans, resulting in an increased incidence and rate of onset of autoimmune diabetes. The data presented in this study highlight the different outcomes of adjuvant administration by different routes. Because dermal application of cholera toxin, and other bacterial products with similar adjuvant activities, is being developed as a clinical vaccination strategy, these data raise the possibility that it could precipitate autoimmune disease in genetically susceptible humans.
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PMID:Dermal enhancement: bacterial products on intact skin induce and augment organ-specific autoimmune disease. 1468 38

Multiple sclerosis (MS) is more prevalent in women than men. We evaluated seven different mouse strains commonly used in the study of autoimmune diseases, for sex differences in the disease course of experimental autoimmune encephalomyelitis (EAE). Greater severity of EAE was observed in the female SJL immunized with two different peptides of myelin proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) as well as in the female ASW relative to males. Female NZW mice showed a greater incidence of EAE than males. However, male B10.PL and PL/J mice showed more severe disease than females. No sex differences were noted in the C57BL/6 or NOD strains.
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PMID:Sex differences in experimental autoimmune encephalomyelitis in multiple murine strains. 1508 Dec 49

Upon stimulation by microbial products through TLR, dendritic cells (DC) acquire the capacity to prime naive T cells and to initiate a proinflammatory immune response. Recently, we have shown that APC within the CNS of multiple sclerosis (MS) patients contain peptidoglycan (PGN), a major cell wall component of Gram-positive bacteria, which signals through TLR and NOD. In this study, we report that Staphylococcus aureus PGN as a single component can support the induction of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model for MS. Mice immunized with an encephalitogenic myelin oligodendrocyte glycoprotein peptide in IFA did not develop EAE. In contrast, addition of PGN to the emulsion was sufficient for priming of autoreactive Th1 cells and development of EAE. In vitro studies demonstrate that PGN stimulates DC-mediated processes, reflected by increased Ag uptake, DC maturation, Th1 cell expansion, activation, and proinflammatory cytokine production. These data indicate that PGN-mediated interactions result in proinflammatory stimulation of Ag-specific effector functions, which are important in the development of EAE. These PGN-mediated processes may occur both within the peripheral lymph nodes as well as in the CNS and likely involve recognition by TLR on DC. Thus, PGN may provide a physiological trigger of DC maturation, and in this way disrupt the normal tolerance to self Ag. As such, PGN signaling pathways may serve as novel targets for the treatment of MS.
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PMID:Proinflammatory bacterial peptidoglycan as a cofactor for the development of central nervous system autoimmune disease. 1563 2

Murine experimental autoimmune encephalomyelitis is a well-established model that recapitulates many clinical and physiopathological aspects of multiple sclerosis (MS). An important conceptual development in the understanding of both experimental autoimmune encephalomyelitis and MS pathogenesis has been the compartmentalization of the mechanistic process into two distinct but overlapping and connected phases, inflammatory and neurodegenerative. However, the dynamics of CNS transcriptional changes that underlie the development and regression of the phenotype are not well understood. Our report presents the first high frequency longitudinal study looking at the earliest transcriptional changes in the CNS of NOD mice immunized with myelin oligodendrocyte glycoprotein 35-55 in CFA. Microarray-based gene expression profiling and histopathological analysis were performed from spinal cord samples obtained at 13 time points around the first clinical symptom (every other day until day 11 and every day onward until day 19 postimmunization). Advanced statistics and data-mining algorithms were used to identify expression signatures that correlated with disease stage and histological profiles. Discrete phases of neuroinflammation were accompanied by distinctive expression signatures, in which altered immune to neural gene expression ratios were observed. By using high frequency gene expression analysis we captured expression profiles that were characteristic of the transition from innate to adaptive immune response in this experimental paradigm between days 11 and 12 postimmunization. Our study demonstrates the utility of large-scale transcriptional studies and advanced data mining to decipher complex biological processes such as those involved in MS and other neurodegenerative disorders.
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PMID:Modular transcriptional activity characterizes the initiation and progression of autoimmune encephalomyelitis. 1590 90

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

During an autoimmune process, the autoaggressive response spreads from the initiating autoantigen to other antigens expressed in the target organ. Based on evidence from experimental models for multiple sclerosis, such "antigenic spreading" can play an important role in the exacerbation of clinical disease. We evaluated whether pathogenesis of spontaneous diabetes in NOD mice could be accelerated in a similar way when a novel autoantigen was expressed in pancreatic beta-cells. Unexpectedly, we found that the expression of the lymphocytic choriomeningitis virus nucleoprotein only led to marginal enhancement of diabetes, although such NOD-nucleoprotein mice were not tolerant to nucleoprotein. Although the frequency of nucleoprotein-specific CD8 T-cells in the pancreatic draining lymph node was comparable with the frequency of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T-cells, more IGRP-specific CD8 T-cells were found both systemically and in the islets where there was a fourfold increase. Interestingly, and in contrast to nucleoprotein-specific CD8 T-cells, IGRP-specific T-cells showed increased CXCR3 expression. Thus, autoreactivity toward de novo-expressed beta-cell autoantigens will not accelerate autoimmunity unless large numbers of antigen-experienced autoreactive T-cells expressing the appropriate chemokine receptors are present.
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PMID:Minimal impact of a de novo-expressed beta-cell autoantigen on spontaneous diabetes development in NOD mice. 1739 46

Multiple sclerosis (MS) is characterized by inflammatory demyelination of axons and neurodegeneration, the latter inadequately modeled in experimental autoimmune encephalomyelitis (EAE). Susceptibility of inbred mouse strains to EAE is in part determined by major histocompatibility complex haplotype; however, other molecular mechanisms remain elusive. Galectins bind GlcNAc-branched N-glycans attached to surface glycoproteins, forming a molecular lattice that restricts lateral movement and endocytosis of glycoproteins. GlcNAc branching negatively regulates T cell activity and autoimmunity, and when absent in neurons, induces apoptosis in vivo in young adult mice. We find that EAE susceptible mouse strains PL/J, SJL, and NOD have reduced GlcNAc branching. PL/J mice display the lowest levels, partial deficiencies in N-acetylglucosaminyltransferase I, II, and V (i.e. Mgat1, -2, and -5), T cell hyperactivity and spontaneous late onset inflammatory demyelination and neurodegeneration; phenotypes markedly enhanced by Mgat5(+/-) and Mgat5(-/-) backgrounds in a gene dose-dependent manner. Spontaneous disease is transferable and characterized by progressive paralysis, tremor, dystonia, neuronophagia, and axonal damage in both demyelinated lesions and normal white matter, phenocopying progressive MS. Our data identify hypomorphic Golgi processing as an inherited trait that determines susceptibility to EAE, provides a unique spontaneous model of MS, and suggests GlcNAc-branching deficiency may promote T cell-mediated demyelination and neurodegeneration in MS.
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PMID:N-glycan processing deficiency promotes spontaneous inflammatory demyelination and neurodegeneration. 1785 38

Axonal degeneration is an important determinant of progressive neurological disability in multiple sclerosis (MS). Thus, therapeutic approaches promoting neuroprotection could aid the treatment of progressive MS. Here, we used what we believe is a novel water-soluble fullerene derivative (ABS-75) attached to an NMDA receptor antagonist, which combines antioxidant and anti-excitotoxic properties, to block axonal damage and reduce disease progression in a chronic progressive EAE model. Fullerene ABS-75 treatment initiated after disease onset reduced the clinical progression of chronic EAE in NOD mice immunized with myelin-oligodendrocyte glycoprotein (MOG). Reduced disease progression in ABS-75-treated mice was associated with reduced axonal loss and demyelination in the spinal cord. Fullerene ABS-75 halted oxidative injury, CD11b+ infiltration, and CCL2 expression in the spinal cord of mice without interfering with antigen-specific T cell responses. In vitro, fullerene ABS-75 protected neurons from oxidative and glutamate-induced injury and restored glutamine synthetase and glutamate transporter expression in astrocytes under inflammatory insult. Glutamine synthetase expression was also increased in the white matter of fullerene ABS-75-treated animals. Our data demonstrate the neuroprotective effect of treatment with a fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of progressive MS and other neurodegenerative diseases.
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PMID:Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. 1834 Mar 79


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