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)

This review surveys the structural terrain of the multiple sclerosis (MS) lesion from the standpoint of its immunologic responsiveness. Similarities in lymphocyte trafficking patterns are noted between MS and its laboratory model, experimental allergic encephalomyelitis (EAE), and in both conditions, the inflammatory response is selective for the central nervous system (CNS). While adhesion molecules abound during the genesis of the MS lesion, none has yet been found that is unusual to this condition and, indeed, many occur in other neurodegenerative states in which inflammation is not a component of the lesion. Cytokines are effective regulators of lymphocyte traffic and adhesion events and most can be located in MS lesions. Of these, tumor necrosis factor-alpha (TNF-alpha) occurs in abundance. Together with its known affinity to effect myelin and oligodendrocyte destruction and to up-regulate adhesion molecule expression, the presence of TNF-alpha renders it an important player in lesion pathogenesis. Demyelination is described as a rapid lytic event, perhaps involving cytokines and immunoglobulin, and structural similarities are common in the patterns seen in MS and EAE. Oligodendrocytes survive the initial stages of lesion formation. Moreover, they are now known to proliferate and elaborate new myelin at the same time as myelin is being degraded. This paradoxical reparatory scenario is apparently a transient event although rims of remyelination persist about the margins of chronic lesions. The speculation is reiterated that the demise of the oligodendrocyte in MS may occur late in lesion formation and may be in part related to the expression of heat shock proteins (specifically, members of the hsp 60 family), potent stimulators of T-cell receptor-gamma delta T cells that have been claimed to have cytolytic activity and that have been located in chronic active MS lesions. In sum, while no single immune system molecule can be assigned as unusual to the CNS in MS, and while there appears to be nothing unique about the manner in which the CNS responds to the inflammation, the true uniqueness of the situation in MS is probably related to the many, normally sequestered, specific antigens within the myelin sheath and the biology of the myelinating cell, the oligodendrocyte.
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PMID:The Dale E. McFarlin Memorial Lecture: the immunology of the multiple sclerosis lesion. 801 91

In order to examine the plasminogen activator (PA) induction involved in the pathogenesis of acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS), PA activity in peripheral blood lymphocytes derived from 5 ADEM and 3 MS patients was investigated. There was no PA induction in any ADEM, MS or control lymphocytes treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) alone. PA activity, however, in lymphocytes exposed to human interferon-gamma (HuIFN-gamma) prior to MNNG treatment was elevated during the active phase of ADEM and MS, whereas the PA induction disappeared in association with improvement of the neurologic symptoms. The PA activity was abolished by mixed treatment with HuIFN-gamma and anti-HuIFN-gamma antibody. No such PA induction by any HuIFN was observed in any normal controls or cases of other neurologic diseases. Among the cytokines tested other than HuIFN, tumor necrosis factor-alpha, in combination with MNNG, also induced PA activity in lymphocytes from ADEM and MS patients during the active phase. Thus, the PA induction observed in lymphocytes on combined treatment with MNNG and cytokines may be involved in the progression of neurologic disorders in these demyelinating diseases, and indicates the possibility of therapeutic strategies involving anticytokine usage.
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PMID:Involvement of cytokines in N-methyl-N'-nitro-N-nitrosoguanidine-induced plasminogen activator activity in acute disseminated encephalomyelitis and multiple sclerosis lymphocytes. 824 10

In order to examine the effect of cytokines on the central nervous system, we injected tumor necrosis factor (TNF) alpha or interleukin-1 (IL-1) alpha into the brains of mice. Although mice injected with saline alone exhibited no inflammatory responses, histopathological studies of mice injected with TNF alpha or IL-1 alpha revealed mild mononuclear cell infiltration around the blood vessels, edema and mild hemorrhage several millimeters distant from the needle track. These findings are similar in pattern to those observed in the early stage of experimental allergic encephalomyelitis (EAE). Increased vascular permeability induced by injections of TNF or IL-1 may play a role in the pathogenesis of these inflammatory responses. The direct cytokine injection model offers a new way of examining the mechanisms of early inflammation in the central nervous system.
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PMID:[Effect of intracerebral injections of tumor necrosis factor and interleukin-1]. 825 Jul 25

The phosphodiesterase inhibitor pentoxifylline (POX), which is known to have pharmacological effects in animal models of multiorgan failure and endotoxin-mediated shock, was tested for its immunosuppressive potential on T lymphocyte activation in vitro and in vivo. POX was found to have a profound inhibitory effect on both mitogen- and antigen-induced proliferation of CD4+ T cells in vitro. This inhibitory activity of the drug could be reproduced by treating T lymphocytes with cAMP analogues during stimulation. Responses of repeatedly in vitro stimulated cells were much more strongly inhibited by the drug and by cAMP analogues than responses of fresh resting lymphocytes. Furthermore, POX could drastically down-regulate tumor necrosis factor regulate production and to a lesser extent interleukin (IL)-2 secretion in activated T cells, but an excess of exogenous IL-2 did not override the antiproliferative effect of the drug. In contrast, the same doses of POX had no inhibitory effect on spontaneous or induced IL-4 and IL-6 production by short-term cultured T lymphocytes, indicating a selective sparing of T helper type 2 (Th2)-associated lymphokine functions by the drug. To test a potential use of POX as an antiinflammatory agent in T cell-mediated autoimmune disease, the influence of POX on myelin basic protein (MBP)-induced experimental autoimmune encephalomyelitis (EAE) was assessed. The onset of EAE in Lewis rats could almost completely be abrogated by oral administration of POX during the induction phase of disease. Lack of clinical symptoms in POX-treated animals coincided with a marked suppression of MBP-specific T cell reactivity in vitro, without any evidence for a generalized impairment of T cell activity. Collectively, our data suggest the potential use of xanthine derivatives of the POX type as a supporting antiinflammatory therapeutic agent in Th1 CD4+ T cell-mediated autoimmune diseases in animal models and possibly in man.
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PMID:Phosphodiesterase inhibitor pentoxifylline, a selective suppressor of T helper type 1- but not type 2-associated lymphokine production, prevents induction of experimental autoimmune encephalomyelitis in Lewis rats. 839 96

We tested the effect of bovine cortex phosphatidylserine (BC-PS), a membrane phospholipid known to inhibit the release of the cytokine tumor necrosis factor (TNF), in SJL/J mice sensitized for adoptively transferred experimental autoimmune encephalomyelitis (EAE). Control, sensitized mice developed severe clinical and histologic EAE within 6 to 9 days, whereas only 20% of mice given BC-PS displayed clinical signs that were much less severe and minimal CNS pathology. Cessation of BC-PS treatment after 15 to 40 days led to disease within 1 to 2 weeks, but when treatment was more prolonged, animals remained healthy after cessation. Serial transfer of spleen cells (SC) from BC-PS-treated and control animals into naive recipients resulted in acute EAE within 6 to 7 days with cells from either donor type. Animals treated late with BC-PS failed to relapse and generally remained healthier than controls did over a 40-day period of observation. Cultures of lymph node cells or SC from BC-PS-treated and control animals showed an 80 to 90% reduction in TNF production in the BC-PS-treated group. Thus, we demonstrate that PS can abrogate or significantly reduce the severity of EAE without permanently inhibiting effector T cells. The approach might be considered a candidate for future therapies of relevance to MS.
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PMID:Phosphatidylserine, a putative inhibitor of tumor necrosis factor, prevents autoimmune demyelination. 842 80

The roles of the B7 receptors, CD80 and CD86, during actively induced experimental allergic encephalomyelitis were examined with specific monoclonal antibodies and CTLA4-Ig. Injection of CTLA4-Ig on day 2 post-immunization resulted in decreased incidence and severity of resultant disease. Anti-CD80 injection on day 2 blocked development of the first disease episode. Subsequent relapses were unaffected. In contrast, injection of anti-CD86 alone had no effect. Surprisingly, combined anti-CD80 + anti-CD86 monoclonal antibody injection on day 2 resulted in marked exacerbation of disease. Examination of cytokine production in the draining lymph node cells demonstrated a reduction in both interferon (IFN)-gamma and interleukin (IL)-2 producing cells, but a dramatic increase in tumor necrosis factor (TNF)-alpha secretion in animals receiving both monoclonal antibodies. These results suggest distinct roles for CD80 and CD86 in the initiation of EAE, resulting in the diverse clinical outcomes observed in this model of EAE.
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PMID:Opposing effects of CTLA4-Ig and anti-CD80 (B7-1) plus anti-CD86 (B7-2) on experimental allergic encephalomyelitis. 864 61

Recent studies demonstrated that administration of a p55-tumor necrosis factor (TNF) receptor IgG-fusion protein (TNFR-IgG) prevented the clinical onset of experimental autoimmune encephalomyelitis but did not alter the number or tissue distribution of autoantigen-specific CD4+ effector T cells which trafficked into the central nervous system. To determine whether specific target tissues of autoimmune damage remain intact after TNFR-IgG treatment despite the presence of inflammatory cells within the tissues, we examined rats with experimental autoimmune uveoretinitis (EAU), as in this model, the main target of autoreactive CD4+ T cells, the retinal rod outer segments (ROS), can be examined readily by light microscopy. As judged by direct ophthalmoscopy, the onset of inflammation in the anterior chamber of the eye in EAU following administration of TNFR-IgG was delayed by 6 days compared to untreated controls, but the magnitude of the response was only slightly less than controls. Histological examination of the retinae and direct assessment of retinal inflammation revealed a disproportionate sparing of ROS in the TNFR-IgG-treated animals despite a level of retinal inflammation not substantially less than controls in which ROS damage was marked. Analysis of retinal leukocytes by immunofluorescence microscopy and flow cytometry indicated that approximately equal numbers of CD4+ alpha beta TCR+ lymphocytes were present in treated and control retinae, more than 30% of CD4+ cells in both experimental groups expressed the CD25 or MRC OX40 activation markers and most cells, which would include the CD4+ T lymphocytes, were activated as evidenced by MHC class II expression. Fewer activated macrophages and granulocytes were present in the treated retinae, possibly reflecting the lower level of tissue damage and subsequent accumulation of these inflammatory cells. The results demonstrate directly that a tissue specifically targeted for autoimmune destruction can be protected despite the influx of fully activated CD4+ T cells.
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PMID:Inhibition of tumor necrosis factor activity minimizes target organ damage in experimental autoimmune uveoretinitis despite quantitatively normal activated T cell traffic to the retina. 864 62

The expression of cell adhesion molecules (CAMs) in the choroid plexus was studied in normal brain and during experimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse during inflammation induced by intracerebral injection of killed Corynebacterium parvum in the C3H/He mouse. Both ICAM-1 and VCAM-1, but not MAdCAM-1, were constitutively expressed on choroid plexus epithelium but not on the fenestrated capillary endothelial cells within the choroid plexus. During EAE, we observed an up-regulation of ICAM-1 and VCAM-1 and de novo expression of MAdCAM-1 on choroid plexus epithelial cells. In contrast, endothelial cells in the choroid plexus were not induced to express any of the investigated CAMs. In in situ hybridization analysis we demonstrated that ICAM-1, VCAM-1, and MAdCAM-1 were locally synthesized and that the amount of their mRNAs increased in the inflamed choroid plexus. In vitro, primary choroid plexus epithelial cells could be induced to express ICAM-1, VCAM-1, and MAdCAM-1 on their surface after treatment with proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1, interferon-gamma, and lipopolysaccharide. To investigate the functional status of the expressed CAMs we performed Stamper-Woodruff binding assays on frozen sections of inflamed and naive brains. ICAM-1, VCAM-1, and MAdCAM-1 expressed in choroid plexus epithelial cells mediated binding of lymphocytes via their known ligands LFA-1 and alpha4-integrin, respectively. The expression of ICAM-1, VCAM-1, and MAdCAM-1 on choroid plexus epithelial cells together with the lack of their expression on the fenestrated choroid plexus endothelium raises the possibility that the epithelial blood-cerebrospinal-fluid barrier plays an important role in the immunosurveillance of the central nervous system.
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PMID:ICAM-1, VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and mediate binding of lymphocytes in vitro. 866 69

The levels of tumor necrosis factor (TNF)-alpha producing cells were analyzed in mice with Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Using an ELISPOT assay, we demonstrate an increase in TNF-alpha producing cells in the spinal cords of TMEV-infected SJL/J mice, especially at an active disease stage. The numbers of TNF-alpha producing cells were extremely high in susceptible SJL/J mice compared with the numbers in resistant BALB/c and C57BL/6 mice. TNF-alpha producing cells were also immunohistochemically identified in active lesions of TMEV-IDD at acute as well as chronic stages. The percentage of TNF-alpha producing cells compared with the total number of cells isolated from spinal cords was higher in TMEV-infected SJL/J mice than resistant BALB/c and C57BL/6 mice. Correspondingly, the level of TNF-alpha was much higher in the culture supernatants of both infiltrating cells in the spinal cords and spleen cells from clinically affected animals than that from similarly treated resistant mice. Treatment of virus-infected mice with a mAb specific for TNF-alpha at the beginning of the onset of disease suppressed the development of the demyelinating disease. These findings suggest that TNF-alpha may play an important role in the pathogenicity of TMEV-IDD.
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PMID:The level of tumor necrosis factor-alpha producing cells in the spinal cord correlates with the degree of Theiler's murine encephalomyelitis virus-induced demyelinating disease. 875 45

Infection with JHMV results in the transcriptional activation of two host cell genes encoding proinflammatory cytokines, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta. Analysis of irradiated mice showed that IL-1 beta mRNA accumulation in the central nervous system was predominantly derived from the mononuclear infiltrate. By contrast, accumulation of TNF-alpha mRNA was unaffected by immunosuppression, suggesting that resident cells were the source of this cytokine. Infected mice were treated with anti-TNF antibody to determine if TNF-alpha contributed to either the encephalomyelitis or demyelination associated with JHMV infection. Surprisingly, neither the cellular infiltrate nor demyelination were affected. In vitro analysis showed that IL-1 beta but not TNF was secreted from JHMV infected macrophages. The absence of TNF secretion is due to a block in translation of the TNF mRNA which accumulates during infection.
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PMID:Transcription and translation of proinflammatory cytokines following JHMV infection. 883 Apr 75


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