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)

Excessive nitric oxide (NO) production from the inducible isoform of nitric oxide synthase (iNOS) has been invoked as a causative factor in many neurodegenerative disorders, including multiple sclerosis. This hypothesis has been supported by in vitro studies showing that glial iNOS expression results in toxic NO concentrations (near 1 microm). To investigate the relevance of such findings, experiments were carried out ex vivo on optic nerves from rats with exacerbated experimental allergic encephalomyelitis, a model of multiple sclerosis. The nerves displayed characteristic immunopathology and expression of iNOS in macrophages and/or microglia and there was overt axonal damage in localized regions of the optic chiasm. The resulting NO levels in the optic nerve were sufficient to cause activation of guanylyl cyclase-coupled NO receptors, resulting in marked cGMP accumulation in axons throughout the nerve. Nevertheless, calibration of cGMP levels against those evoked by exogenous NO indicated that the nerves were not compromised metabolically and that their ambient NO concentration was only approximately 1 nm. Consistent with this observation, electrophysiological tests indicated that there was no ongoing malfunctioning of the type that can be elicited by high exogenous NO concentrations. It is concluded that, with iNOS expressed in physiological locations and levels, the tissue levels of NO remain at concentrations far lower than those shown to have toxic effects, despite continuous NO synthesis. The fact that NO can rise to much higher levels in dispersed cultures in vitro may be attributable to a deficiency in NO inactivation in such preparations.
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PMID:Pathological implications of iNOS expression in central white matter: an ex vivo study of optic nerves from rats with experimental allergic encephalomyelitis. 1586 9

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligodendrocyte damage and subsequent axonal demyelination is a hallmark of this disease. Different pathomechanisms, for example, immune-mediated inflammation, oxidative stress and excitotoxicity, are involved in the immunopathology of MS. The risk of developing MS is associated with increased dietary intake of saturated fatty acids. Polyunsaturated fatty acid (PUFA) and antioxidant deficiencies along with decreased cellular antioxidant defence mechanisms have been observed in MS patients. Furthermore, antioxidant and PUFA treatment in experimental allergic encephalomyelitis, an animal model of MS, decreased the clinical signs of disease. Low-molecular-weight antioxidants may support cellular antioxidant defences in various ways, including radical scavenging, interfering with gene transcription, protein expression, enzyme activity and by metal chelation. PUFAs may not only exert immunosuppressive actions through their incorporation in immune cells but also may affect cell function within the CNS. Both dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.
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PMID:Antioxidants and polyunsaturated fatty acids in multiple sclerosis. 1611 55

Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T-cell mediated disease, which resembles immunopathology of multiple sclerosis (MS). Interleukin (IL)-16 is a CD4+ cell-specific chemoattractant cytokine. In CD4+ T cells, production of bioactive IL-16 from constitutive pro-IL-16 requires cleavage by active caspase-3. We reported reversal of established relapsing disease by IL-16 neutralization. To better understand role(s) of IL-16 in regulation of relapsing EAE, we comparatively analyzed levels of IL-16, active caspase-3 and CD4 in mice with severe relapsing-remitting [(B6xSJL) F1], and low-relapsing (B6), disease. Elevated levels of IL-16 along with an increase in active-caspase-3 and CD4 levels correlated with stages of clinically active disease in both strains. CNS levels of bioactive IL-16 were notably higher in F1 compared to B6 mice at all stages, being most prominent during relapse. Similar patterns of regulation for IL-16 and active caspase-3 were observed in peripheral lymphoid organs, and in T cells isolated from lymph nodes following T-cell activation in vitro. IL-16 was co-immunoprecipitated with CD4 from CNS of relapsing mice. Our data suggest that caspase-3 mediated production of IL-16 by infiltrating CD4+ T cells, contributes to ongoing neuroinflammation by chemoattraction of additional waves of CD4+ T cells.
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PMID:Increased levels of bioactive IL-16 correlate with disease activity during relapsing experimental autoimmune encephalomyelitis (EAE). 1627 Dec 92

IL-23 is regarded as a major pro-inflammatory mediator in autoimmune disease, a role which until recently was ascribed to its related cytokine IL-12. IL-23, an IL-12p40/p19 heterodimeric protein, binds to IL-12Rbeta1/IL-23R receptor complexes. Mice deficient for p19, p40 or IL-12Rbeta1 are resistant to experimental autoimmune encephalomyelitis or collagen-induced arthritis. Paradoxically, however, IL-12Rbeta2- and IL-12p35-deficient mice show remarkable increases in disease susceptibility, suggesting divergent roles of IL-23 and IL-12 in modulating inflammatory processes. IL-23 induces IL-17, which mediates inflammation and tissue remodeling, but the role of IL-12 in this respect remains unidentified. We investigated the roles of exogenous (recombinant) and endogenous (macrophage-derived) IL-12 and IL-23, on IL-17-induction in human T-cells. IL-23 enhanced IL-17 secretion, as did IL-2, IL-15, IL-18 and IL-21. In contrast, IL-12 mediated specific inhibition of IL-17 production. These data support the role of IL-23 in inflammation through stimulating IL-17 production by T lymphocytes, and importantly indicate a novel regulatory function for IL-12 by specifically suppressing IL-17 secretion. These data therefore extend previous reports that had indicated unique functions for IL-23 and IL-12 due to distinct receptor expression and signal transduction complexes, and provide novel insights into the regulation of immunity, inflammation and immunopathology.
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PMID:Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. 1648 11

We examine here the outcome of viral encephalomyelitis [mouse hepatitis virus (MHV) A59, Theiler's encephalomyelitis virus, and Coxsackievirus B3] in mice with autoantibodies to a central nervous system (CNS)-specific antigen, myelin oligodendrocyte glycoprotein, that usually develop no clinical disease. Morbidity and mortality of the acute viral CNS disease was augmented by the presence of the autoantibodies in all three viral infections. Transfer of serum containing the autoantibodies at the time of infection with MHV was sufficient to reproduce the exacerbated disease. The presence of the autoantibodies was found to result in increased infiltration of mononuclear cells into the brain. Early demyelination was severely augmented in brains and spinal cords of MHV-infected mice with CNS-specific autoantibodies. The antibody-mediated exacerbation was shown to be independent of the complement system but to require expression of Fc receptors, because it was observed in C'-3-deficient but not in Fc receptor-deficient mice. Our study illustrates the possibility that infections can lead to much more profound immunopathology in the presence of an otherwise latent autoimmune condition.
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PMID:Exacerbated pathology of viral encephalitis in mice with central nervous system-specific autoantibodies. 1725 11

TGF-beta1 is a regulatory cytokine with a pleiotropic role in immune responses. TGF-beta1 is widely expressed in leukocytes and stromal cells. However, the functions of TGF-beta1 expressed by specific lineages of cells remain unknown in vivo. Here, we show that mice with a T cell-specific deletion of the Tgfb1 gene developed lethal immunopathology in multiple organs, and this development was associated with enhanced T cell proliferation, activation, and CD4+ T cell differentiation into T helper 1 (Th1) and Th2 cells. TGF-beta1 produced by Foxp3-expressing regulatory T cells was required to inhibit Th1-cell differentiation and inflammatory-bowel disease in a transfer model. In addition, T cell-produced TGF-beta1 promoted Th17-cell differentiation and was indispensable for the induction of experimental autoimmune encephalomyelitis. These findings reveal essential roles for T cell-produced TGF-beta1 in controlling differentiation of T helper cells and controlling inflammatory diseases.
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PMID:T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. 1752 82

Autoimmunity and tumor immunity evolved as two distinct arenas in immunological research. However, the identification of self-antigens as the major components of malignant cells may define a central role for autoimmunity in cancer control tuned by peripheral immunoregulatory mechanisms avoiding self-aggression. Emerging evidence documents a triple antagonistic role of interleukin-2 (IL-2) in vivo promoting survival, apoptosis, and the generation of regulatory T cells. We have found that IL-2 administration reduces the clinical course of experimental autoimmune encephalomyelitis and enhances immunoregulation in tumor-bearing mice. However, actively induced anti-IL-2 antibodies restore the response to nominal antigens in tumor-induced immunosuppressed host and induced therapeutic effect in transplantable and chemically induced tumors. It is suggested that IL-2 may contribute dynamically to the maintenance of natural immunological tolerance, preventing pathological autoimmunity, but may affect antitumor immunity. Cancer research has gained from autoimmunity understanding that tumor escape strategies include the natural mechanisms of immune tolerance and the ways to imbalance the peripheral regulatory mechanisms. Interestingly, therapeutic manipulations of immunoregulation have limited antitumor effects, although promoting collaterally infrequent autoimmune diseases. It may suggest that tumors may reinforce tolerance to protect themselves from the immune attack, a process that may involve dynamically various mechanisms including IL-2. Understanding this acquired experience from tumors may help utilize them to revert the immunopathology in autoimmune diseases.
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PMID:Interleukin-2 mastering regulation in cancer and autoimmunity. 1780 52

Experimental autoimmune encephalomyelitis (EAE) is a model of the neuroimmune system responding to priming with central nervous system (CNS)-restricted antigens. It is an excellent model of post-vaccinal encephalitis and a useful model of many aspects of multiple sclerosis. EAE has been established in numerous species and is induced by priming with a large number of CNS-derived antigens. As a consequence, the pathogenesis, pathology and clinical signs vary significantly between experimental protocols. As I describe in this Timeline article, the reductionist approach taken in some lines of investigation of EAE resulted in a reliance on results obtained under a narrow range of conditions. Although such studies made important contributions to our molecular understanding of inflammation, T-cell activation, and MHC restriction, they did not advance as effectively our knowledge of the polyantigenic responses that usually occur in CNS immunopathology and autoimmunity.
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PMID:The origin and application of experimental autoimmune encephalomyelitis. 1791 72

This review examines the efficacy of photodynamic therapy in the treatment of immunological disorders. Photodynamic therapy (PDT) is a 2-step procedure. Firstly, a photosensitiser is introduced into the body, where it accumulates selectively in cells with elevated metabolism, such as cancer cells or activated cells of the immune system. Second, light is applied at a wavelength that excites the photosensitiser, producing a variety of short-lived oxygen-derived species. The effect is dependent on the doses of both photosensitiser and activating light. The mechanisms of action of PDT are multifactorial. Induction of high levels of oxidative stress results in necrotic cell death, while lower intensity oxidative stress initiates apoptosis. Sublethal doses may result in the modification of cell surface receptor expression levels and cytokine release and consequently influence cell behaviour. Immunomodulatory PDT (IPDT) utilises mainly apoptotic and sublethal doses. The studies reported here utilise verteporfin, a benzoporphyrin-derived chlorin-like photosensitiser. Veteporfin is a second generation photosensitiser, displaying rapid clearance and consequently a reduced period of skin photosensitivity compared with the first generation photosensitiser, porfimer sodium. In vivo studies showed that IPDT was effective in alleviating immunopathology in murine models of arthritis, contact hypersensitivity, experimental allergic encephalomyelitis and retention of allogeneic skin grafts. Based on these findings, early stage clinical trials with IPDT were initiated recently for the treatment of psoriasis, psoriatic arthritis and rheumatoid arthritis. While verteporfin has been the photosensitiser which pioneered IPDT, a new benzoporphyrin derivative photosensitiser, QLT0074, is under development. This has demonstrated an enhanced avidity for target cells as well as improved clearance characteristics.
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PMID:Photodynamic therapy in immune (non-oncological) disorders: focus on benzoporphyrin derivatives. 1803 64

DR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain-containing tumor necrosis factor (TNF)-family receptor primarily expressed on T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, for polarization into T helper 1 (Th1), Th2, or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 expression was required on T cells for immunopathology, local T cell accumulation, and cytokine production in Experimental Autoimmune Encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. DR3 could be an attractive therapeutic target for T cell-mediated autoimmune and allergic diseases.
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PMID:The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. 1857 43


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