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)

Mucosal administration of low doses of myelin basic protein (MBP) peptide 68-86 (MBP 68-86) or anti-inflammatory cytokine IL-10 effectively prevented experimental allergic encephalomyelitis (EAE), but failed to suppress the disease if given after 7 days postimmunization (p.i.), i.e., after T cell priming had occurred. We anticipated that combined administration of autoantigen and IL-10 can treat incipient EAE. Lewis rats with EAE actively induced with MBP 68-86 and complete Freund's adjuvant received 120 microg MBP 68-86 + 200 ng IL-10 per rat per day from day 7 p.i. and for 5 consecutive days. These rats showed later onset, lower clinical scores, less body weight loss, and shorter duration of EAE than rats receiving MBP 68-86 or IL-10 only or PBS. EAE amelioration was associated with decreased infiltration of ED1(+) macrophages and CD4(+) T cells within the central nervous system and with decreased proliferative responses of lymph node cells, indicating that combined administration of MBP 68-86 and IL-10 induced immune hyporesponsiveness. IFN-gamma secretion as well as IFN-gamma, TNF-alpha, IL-4, and IL-10 mRNA expression by lymph node MNC was down-regulated in the treated rats. Immune hyporesponsiveness, rather than immune deviation or regulatory mechanisms, seems to be responsible for the protection of EAE after autoantigen + IL-10 administration by the nasal route.
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PMID:Combined nasal administration of encephalitogenic myelin basic protein peptide 68-86 and IL-10 suppressed incipient experimental allergic encephalomyelitis in Lewis rats. 1096 38

NO is involved in the regulation of immune responses. The role of NO in the pathogenesis of experimental allergic encephalomyelitis (EAE) is controversial. In this study, 3-morpholinosydnonimine (SIN-1), an NO donor, was administered to Lewis rats on days 5-7 postimmunization, i.e., during the incipient phase of EAE. SIN-1 reduced clinical signs of EAE compared with those in PBS-treated control rats and was accompanied by reduced ED1(+) macrophages and CD4(+) T cell infiltration within the CNS. Blood mononuclear cells (MNC) obtained on day 14 postimmunization revealed that SIN-1 administration enhanced NO and IFN-gamma production by blood MNC and suppressed Ag- and mitogen-induced proliferative responses. MHC class II, B7-1 and B7-2 were down-regulated in SIN-1-treated EAE rats. Simultaneously, frequencies of apoptotic cells among blood MNC were increased. In vivo, SIN-1 is likely to behave as an NO donor. Administration of SIN-1 induced NO production, but did not affect superoxide and peroxynitrite formation. Enhanced NO production during the priming phase of EAE thus promotes apoptosis, down-regulates disease-promoting immune reactivities, and ameliorates clinical EAE, mainly through SIN-1-derived NO, without depending on NO synthase.
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PMID:SIN-1, a nitric oxide donor, ameliorates experimental allergic encephalomyelitis in Lewis rats in the incipient phase: the importance of the time window. 1131 25

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterised by a disruption of the blood-brain barrier (BBB), demyelination and a relevant inflammatory reaction with an intense infiltration of macrophages. These neurological disorders are similar to those observed in the multiple sclerosis (MS) disease. The use of different liposomes and adeno-associated virus has been proposed for improving the treatment of this pathogenesis. The aim of this work was to evaluate the potential and capacity of albumin nanoparticles to reach the central nervous system (CNS) in EAE-induced rats. For this purpose, the distribution of biotinylated nanoparticles within the CNS was studied. Albumin carriers were mainly found in the lumbar portion of the spinal cord, overlying the meningeal and perivascular areas. The optic chiasma, iris and the area of the Purkinje cells of the cerebellum revealed also an intense presence of these carriers. Finally, immunohistochemical studies also revealed that circulating macrophages (ED1), which migrate to damaged sites, and resident activated microglial cells (OX42) were involved in the distribution of albumin nanoparticles. In summary, the use of nanoparticles may be useful for the design of new pharmaceutical dosage forms able to target the lesions associated with alterations of the BBB.
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PMID:Distribution of albumin nanoparticles in animals induced with the experimental allergic encephalomyelitis. 1132 57

The involvement of inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-alpha), which have diverse roles in the progression of autoimmune disease models, was studied in pertussis toxin (PT)-induced hyperacute experimental autoimmune encephalomyelitis (EAE) in Lewis rats. The expression of TNF-alpha mRNA (increased 5-fold, P<0.01) and iNOS protein (3-fold, P<0.01) was much greater in the spinal cords with PT(+) EAE at the peak stage of EAE than in those with PT(-) EAE, as shown by competitive PCR and Western blot analysis, respectively. Immunohistochemistry showed that the majority of ED1-positive macrophages in EAE lesions contained iNOS, and that there were many more iNOS-positive cells in the CNS lesions of PT(+) rats than in those of PT(-) rats. These findings suggest that PT-induced hyperacute EAE is partly mediated by the enhanced expression of iNOS and TNF-alpha in the early stages of rat EAE.
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PMID:Pertussis toxin-induced hyperacute autoimmune encephalomyelitis in Lewis rats is correlated with increased expression of inducible nitric oxide synthase and tumor necrosis factor alpha. 1144 81

Phospholipase D1 (PLD1) expression was studied in the central nervous system (CNS) under the condition of induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats. After inducing EAE, the expression of PLD1 was analyzed by Western blot and immunohistochemistry. Western blot analysis showed that expression of the isozymes PLD1 significantly increased in the spinal cord at the peak stage of EAE, and declined thereafter. Immunohistochemistry showed that PLD1-positive cells increased in number in EAE lesions, which consisted mainly of ED1-positive macrophages and glial fibrillary acidic protein-positive astrocytes. In contrast, PLD1 was only weakly expressed in some spinal cord astrocytes in control rats. These results suggest that PLD1 is increased in autoimmune CNS inflammation, and possibly involved in the activation of macrophages and astrocytes in EAE lesions.
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PMID:Increased expression of phospholipase D1 in the spinal cords of rats with experimental autoimmune encephalomyelitis. 1174 24

Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats is a chronic inflammatory demyelinating disease of the central nervous system (CNS) strongly mimicking multiple sclerosis (MS). We determined the involvement of macrophages and microglia in the lesions of MOG-EAE in relation to different major histocompatibility complex (MHC, RT1 in rat) haplotypes. We used intra-RT1 recombinant rat strains with recombinations between the RT1a and RT1u haplotypes on the disease permissive LEW non-MHC genome. Activated microglia and macrophages were identified morphologically and by expression of ED1 and allograft inhibitory factor-1 (AIF-1), and differentiated by their morphological phenotype. White matter lesions contained more macrophages and less microglia compared to grey matter lesions. Similarly active lesions were mainly infiltrated by macrophages, while microglia were abundant in inactive demyelinated plaques. In addition, we found a highly significant genetic association between a macrophage or microglia dominated lesional phenotype, which was independent from location and activity of the lesions. This was not only the case in demyelinating plaques of chronic EAE, but also in purely inflammatory lesions of acute passive transfer EAE. Rat strains with an u-haplotype in both the Class II and the telomeric non-classical Class I region revealed inflammatory and demyelinating lesions, which were dominated by activated microglia. The a-haplotype in any of these regions was associated with macrophage dominated lesions. A comparison of lesions, exactly matched for stages of demyelinating activity in these different rat strains, showed that in spite of a similar extent of demyelination, axonal injury was significantly less in microglia compared to macrophage dominated lesions. Thus, our studies document a genetic influence of the MHC-region on the relative contribution of macrophages versus microglia in the pathogenesis of EAE.
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PMID:MHC gene related effects on microglia and macrophages in experimental autoimmune encephalomyelitis determine the extent of axonal injury. 1214 97

Increasing evidence suggests an important role of CD8(+) cells in the pathogenesis of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). In our present study we analyzed the spatiotemporal expression pattern of the CD8 antigen in various rat EAE models characterized by a different extent of inflammation, demyelination, and axonal injury. Unexpectedly, in chronic demyelinating EAE induced by immunization against myelin oligodendrocyte glycoprotein (MOG) the majority of CD8 immunoreactivity was expressed on ED1(+) microglia/macrophages whereas only limited CD8(+) T-cell infiltration was present. CD8(+) phagocyte recruitment was restricted to sites of severe inflammatory tissue destruction. Contrastingly, macrophages in a perivascular or submeningeal position and in secondarily degenerating fiber tracts were mostly CD8(-). CD8(+) phagocytes were absent in myelin basic protein-induced EAE characterized by a purely inflammatory pathology and lack of demyelination. Our data demonstrate significant heterogeneity of lesion-associated phagocytes in rat models of central nervous system autoimmune disease and suggest a specific role of CD8(+) microglia/macrophages in the pathogenesis of inflammatory tissue damage.
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PMID:CD8+ phagocyte recruitment in rat experimental autoimmune encephalomyelitis: association with inflammatory tissue destruction. 1450 58

To investigate whether the phosphorylation of cyclic AMP response element-binding protein (CREB) is implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the change in the level of CREB phosphorylation was analyzed in the spinal cord of Lewis rats with EAE. Western blot analysis showed that the phosphorylation of CREB in the spinal cord of rats increased significantly at the peak stage of EAE compared with the controls (p<0.05) and declined significantly in the recovery stage (p<0.05). Immunohistochemistry showed that the phosphorylated form of CREB (p-CREB) was constitutively immunostained in few astrocytes and dorsal horn neurons in the spinal cord of normal rats. In the EAE-affected spinal cord, p-CREB was mainly found in ED1-positive macrophages at the peak stage of EAE, and the number of p-CREB-immunopositive astrocytes was markedly increased in the spinal cord with EAE compared with the controls. Moreover, p-CREB immunoreactivity of sensory neurons, which are closely associated with neuropathic pain, was significantly increased in the dorsal horns at the peak stage of EAE. Based on these results, we suggest that the increased phosphorylation of CREB in EAE lesions was mainly attributable to the infiltration of inflammatory cells and astrogliosis, possibly activating gene transcription, and that its increase in the sensory neurons in the dorsal horns is involved in the generation of neuropathic pain in the rat EAE model.
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PMID:Increased phosphorylation of cyclic AMP response element-binding protein in the spinal cord of Lewis rats with experimental autoimmune encephalomyelitis. 1761 86

The importance of the IL-12/IFN-gamma/nitric oxide (NO) axis in the pathogenesis of autoimmune diseases remains controversial. In parallel experiments, we explored the role of the IL-12/IFN-gamma/NO axis in the development of MOG 35-55-induced experimental autoimmune encephalomyelitis (EAE) in mice lacking IL-12, IFN-gamma receptor (IFN-gammaR) and inducible nitric oxide synthase (NOS2), respectively. In comparison with wide-type control mice, IL-12-/-, IFN-gammaR-/- and NOS2-/- mice displayed more severe clinical signs of EAE both in remission and at subsequent relapse. Given the relatively low IFN-gamma production in IL-12-/- mice and the lack of IFN-gamma/IFN-gammaR signaling pathway in IFN-gammaR-/- mice, IL-12-/-, IFN-gammaR-/- and NOS2-/- mice with EAE exhibited low NO production. This correlated negatively with MOG 35-55-induced T cell proliferation. Both ED1-positive macrophages and CD4-positive T cells were increased in spinal cords from IL-12-/-, IFN-gammaR-/- and NOS2-/- compared to control mice. In vitro experiments demonstrate that spleen mononuclear cells from IL-12-/-, IFN-gammaR-/- and NOS2-/-mice with EAE present stronger migration capacity when compared to control mice. These results reveal that the IL-12/IFN-gamma/NO axis plays a critical role in the development of MOG 35-55-induced EAE, possibly over failing NO production.
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PMID:IL-12/IFN-gamma/NO axis plays critical role in development of Th1-mediated experimental autoimmune encephalomyelitis. 1769 13

Recently macrophages were shown to play a protective role in retinal ganglion cells (RGCs) after optic nerve (ON) injury. In the present study, we investigated how macrophages responded after acute intraocular pressure (IOP) elevation in experimental autoimmune encephalomyelitis (EAE)-resistant Fischer 344 (F344) and Sprague Dawley (SD) rats and EAE-vulnerable Lewis rats. Acute IOP elevation was performed at 110mmHg for 2h to mimic acute glaucoma. Phagocytic cells in the eye were removed by intravitreal application of clodronate liposomes whereas macrophage activation was achieved by intravitreal injection of zymosan, a yeast wall preparation. Fluorescence dye, FluoroGold, was applied behind the eyeballs to retrogradely label surviving RGCs 40h before animal sacrifice. Macrophages in the retina were identified by ED1 immunostaining. Loss of 25% RGCs in F344 but over 90% in Lewis rats was seen 2 weeks after acute IOP elevation. Significant increase in the number of macrophages in the retina was seen to accompany the great RGC loss in Lewis rats; removal of these macrophages reduced the extent of RGC loss, suggesting the involvement of macrophages in RGC death in Lewis strain. Low numbers of macrophages were seen in F344 retinas after acute IOP elevation, and removal of macrophages did not show clear effect on RGC viability. Whereas macrophage activation by zymosan protected RGCs after ON axotomy in F344 rats, the same macrophage activation became detrimental to RGCs after acute IOP elevation. The extent of RGC loss 3 weeks after acute IOP elevation or after macrophage activation by zymosan in EAE-resistant SD rats was similar to that in F344 rats. We thus demonstrate that macrophages in rats with different autoimmune backgrounds react differently to acute IOP elevation and differentially modulate RGC loss, a phenomenon contrary to the protective action in RGCs after ON axotomy. These data suggest that autoimmune background plays a role in modulating vulnerability of RGCs to acute IOP elevation.
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PMID:Different responses of macrophages in retinal ganglion cell survival after acute ocular hypertension in rats with different autoimmune backgrounds. 1782 87


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