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)

Among its varied functions, Notch signaling is involved in peripheral T cells responses. The activation and polarization of CD4(+) T cells toward a Th1 lineage are essential steps in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Inhibition of all four Notch receptors with a gamma-secretase inhibitor was shown to block Th1-type polarization and to attenuate the symptoms of experimental autoimmune encephalomyelitis. In this study, we have examined the role of individual Notch receptors in proliferation, cytokine production, and encephalitogenic potential of PLP-reactive T cells. Specific induction of Notch1 and Notch3 transcripts were noted in PLP-reactive T cells upon Ag stimulation. However, using gamma-secretase inhibitor and Abs blocking distinct Notch receptors, we have found that selective inhibition of Notch3, but not Notch1, receptor abrogated proliferation, Th1- and Th17-type responses of PLP-reactive T cells. Moreover, Notch3 inhibition in T cells correlated with the down-regulated expression of protein kinase Ctheta, a kinase with important regulatory function within mature T cells. Thus, selective inhibition of the Notch3 receptor may have important effects on peripheral T cell responses and may offer a new attractive target in treating autoimmune diseases, including multiple sclerosis.
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PMID:Notch3 inhibition in myelin-reactive T cells down-regulates protein kinase C theta and attenuates experimental autoimmune encephalomyelitis. 1825 Apr 75

Multiple sclerosis (MS) is a chronic neurodegenerative disease that causes central nervous system (CNS) inflammation and demyelination, affecting approximately two million people worldwide. In humans, different subtypes of the disease have been noted, characterized by distinct clinical courses and different histopathological manifestations. These disease variants likely result from the targeting of different neuroantigens in the CNS and possibly from the involvement of different effector arms of the immune system such as CD4(+) and CD8(+) T cells as well as autoantibodies. Mechanistic studies addressing the pathomechanisms of MS involve experimental autoimmune encephalomyelitis (EAE) in which immunization with neuroantigens is used to elicit the disease. Mechanism-oriented studies of EAE rely mostly on gene-modified mice on the C57BL/6 (B6) background. Here, we discuss how a systematic immuno- and histopathological comparison of the presently available EAE models on the B6 background, i.e. myelin basic protein-proteolipid protein (MBP-PLP) fusion protein (MP4)-, myelin oligodendrocyte glycoprotein (MOG) peptide 35-55- and PLP peptide 178-191-induced EAE, can facilitate our understanding of the complexity of MS. We point out how the development of further models on this basis can help cover the plethora of disease manifestations seen in MS.
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PMID:Comparing the CNS morphology and immunobiology of different EAE models in C57BL/6 mice - a step towards understanding the complexity of multiple sclerosis. 1834 37

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS. The numbers of autoimmune T cells and Abs specific for proteins of CNS myelin are increased in the blood in some patients with MS. The aim of this study was to investigate whether there are correlations between the specificity of the autoimmune responses in the blood, the HLA molecules carried by the patient, and the clinical features of MS, because studies on experimental autoimmune encephalomyelitis, an animal model of MS, indicate that autoimmune responses targeting particular myelin proteins and the genetic background of the animal play a role in determining the pattern of lesion distribution. We tested blood T cell immunoreactivity to myelin proteins in 100 MS patients, 70 healthy controls, and 48 patients with other neurological disorders. Forty MS patients had strongly increased T cell reactivity to one or more myelin Ags. In these 40 patients, the most robust correlation was between CD4(+) T cell reactivity to myelin proteolipid protein residues 184-209 (PLP(184-209)) and development of lesions in the brainstem and cerebellum. Furthermore, carriage of HLA-DR4, -DR7, or -DR13 molecules by MS patients correlated with increased blood T cell immunoreactivity to PLP(184-209), as well as the development of lesions in the brainstem and cerebellum. Levels of PLP(190-209)-specific Abs in the blood also correlated with the presence of cerebellar lesions. These findings show that circulating T cells and Abs reactive against specific myelin Ags can correlate with lesion distribution in MS and suggest that they are of pathogenic relevance.
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PMID:Correlation of blood T cell and antibody reactivity to myelin proteins with HLA type and lesion localization in multiple sclerosis. 1842 64

Multiple sclerosis (MS) is characterized by a dynamic inflammatory process in which CNS lesions of distinct cellular composition coexist. In particular the formation of B cell plaques has been ascribed an important role as predictor of disease progression. Here we show that the novel MBP-PLP fusion protein (MP4)-induced experimental autoimmune encephalomyelitis (EAE) of C57BL/6 mice fulfils these criteria inducing differential cellular infiltration of B cells, T cells, macrophages and granulocytes and permitting the quantification and staging of the disease. On the contrary, both key features - dynamic CNS inflammation and B cell infiltration - were absent in the classical MOG:35-55-induced EAE of C57BL/6 mice, which was characterized by a static CD4(+) T cell and macrophage-mediated CNS immunopathology throughout the disease. MP4-induced EAE may thus provide a unique opportunity for studying immune-pathomechanisms of the disease that have been previously neglected due to experimental shortcomings in murine EAE.
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PMID:Fundamental differences in the dynamics of CNS lesion development and composition in MP4- and MOG peptide 35-55-induced experimental autoimmune encephalomyelitis. 1872 16

Experimental autoimmune encephalomyelitis (EAE), an animal model of Multiple Sclerosis, is induced after injection of PLP(139-151) myelin peptide in complete Freund's adjuvant into SJL/J mice. During EAE, T cells and macrophages infiltrate the brain, produce cytokines IL-17, IFN-gamma, TNF-alpha, or IL-6, and bring about autoimmune neuroinflammation. However, infiltrating T cells which simultaneously produce IL-17 and IL-10 or infiltrating CD4(-) NKT cells that produce IFN-gamma protect against EAE. Resveratrol, a plant polyphenol, exhibits anti-inflammatory properties. To determine if resveratrol can relieve EAE, SJL/J mice were administered diets enriched in resveratrol at EAE injection. EAE symptoms were significantly less compared with controls in mice fed resveratrol. At day 56 of EAE, splenic T cells from mice fed 0%, 0.04% or 0.08% resveratrol that were restimulated with PLP(139-151) produced similar levels while splenic T cells from mice fed 0.02% resveratrol produced significantly higher levels of IL-17, IFN-gamma, and TNF-alpha. At peak EAE (day 14), mice fed resveratrol had higher numbers of IL-17+ T cells, IL-17+/IL-10+ T cells, and CD4(-)IFN-gamma+ cells in the brain and spleen compared with controls. Adoptive transfer of day 14 EAE encephalogenic T cells into mice fed resveratrol reduced the severity of EAE. In addition, resveratrol directly suppressed expression of IL-6 and IL-12/23 p40 but increased expression of IL-12 p35 and IL-23 p19 from macrophages. Therefore resveratrol protection against EAE is not associated with declines in IL-17+ T cells but is associated with rises in IL-17+/IL-10+ T cells and CD4(-)IFN-gamma+ and with repressed macrophage IL-6 and IL-12/23 p40 expression.
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PMID:Decreased severity of experimental autoimmune encephalomyelitis during resveratrol administration is associated with increased IL-17+IL-10+ T cells, CD4(-) IFN-gamma+ cells, and decreased macrophage IL-6 expression. 1902 3

Among all of the genetic factors associated with multiple sclerosis (MS) susceptibility, MHC class II molecules have the strongest association. Although a direct role of DR alleles in MS have been confirmed, it has been difficult to understand the role of DQ alleles in disease pathogenesis due to strong linkage disequilibrium with certain DR alleles. Population studies have indicated that DQ alleles may play a modulatory role in progression of MS. Using HLA class II transgenic (Tg) mice, we investigated gene complementation between DR and DQ genes in the disease process. Previously, using single Tg mice (expressing HLA-DR or DQ gene), we showed that PLP(91-110) peptide induced experimental autoimmune encephalomyelitis (EAE) only in DR3.Abeta degrees mice, suggesting that DR3 (DRB1*0301) is a disease susceptibility gene in the context of PLP. We also showed that DQ6 protects development of EAE in DQ6/DR3 double Tg mice by production of anti-inflammatory IFN-gamma. In this study, we investigated the ability of DQ8 to modulate disease in DR3/DQ8 double Tg mice. Introduction of DQ8 onto DR3 Tg mice led to higher disease incidence and increased disease severity on immunization with PLP(91-110), indicating that DQ8 had an exacerbating effect on the development of EAE. Increased susceptibility in DR3/DQ8 Tg mice was due to increased production of proinflammatory cytokine IL-17 by DQ8-restricted T cells. HLA-DR3/DQ8 mice with EAE also demonstrated increased inflammation and demyelination in CNS as compared with single DR3 Tg mice. Thus double Tg mouse provides a novel model to study epistatic interactions between HLA class II molecules in inflammatory and demyelinating disease.
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PMID:HLA-DQ8 (DQB1*0302)-restricted Th17 cells exacerbate experimental autoimmune encephalomyelitis in HLA-DR3-transgenic mice. 1934 94

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is neuroprotective in animal models of neurodegenerative diseases. However, BDNF has a short half-life and its efficacy in the central nervous system (CNS), when delivered peripherally, is limited due to the blood-brain barrier (BBB). We have developed a means of delivering BDNF into the CNS using genetically engineered bone marrow stem cells (BMSCs) as a vehicle, and have explored the clinical effects of BDNF on outcomes in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). BDNF-engineered-BMSCs were transplanted (i.v.) into irradiated 2-week-old SJL/J female mice. Eight weeks after transplantation, mice were immunized with a peptide of proteolipid protein (PLP(139-151)). Mice, which had received BDNFengineered BMSCs, showed a significant delay in EAE onset and a reduction in overall clinical severity compared to mice receiving BMSC transfected with an empty vector lacking the BDNF gene. In addition, pathological examination showed that BDNF delivery reduced demyelination and increased remyelination. Inhibition of pro-inflammatory cytokines TNF-alpha and IFN-gamma and enhanced expression of the antiinflammatory cytokines IL-4, IL-10, and IL-11 were found in the CNS tissues of the BDNF transplanted group. These results support the use of BMSCs as vehicles to deliver BDNF into the CNS of EAE animals. This is a potentially novel therapeutic approach that might be used to deliver BDNF gene or genes for other therapeutic proteins into the CNS in MS or in other diseases of the CNS in which accessibility of therapeutic proteins is limited due to the BBB.
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PMID:Brain-derived neurotrophic factor gene delivery in an animal model of multiple sclerosis using bone marrow stem cells as a vehicle. 1936 71

Multiple sclerosis (MS) is a human CNS autoimmune demyelinating disease. Epidemiological evidence has suggested a role for virus infection in the initiation and/or exacerbation of MS. Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease serves as a relevant mouse model for MS. TMEV-infected mice develop a demyelinating disease with clinical symptoms beginning around 35 days after infection, which is associated with development of myelin-specific, PLP(139-151), CD4(+) T cell responses. Viruses have been suggested to initiate autoimmune disease through bystander activation of immune cells or through bystander damage to tissue during infection. We examined the effect of the innate immune response on development of autoimmune demyelinating disease by altering the innate immune response through administration of innate immune cytokines, IFN-alpha or IFN-beta, or antiserum against the type I IFNs during the innate immune response to TMEV. Administration of IFN-beta, but not IFN-alpha, to TMEV- infected mice led to reduced myelin-specific CD4(+) T cell responses and reduced demyelinating disease, which was associated with decreased immune cell infiltration into the CNS and increased expression of IL-10 in the CNS. Conversely, administration of antiserum to IFN-beta led to a more severe demyelinating disease. In addition, administration of poly(I:C), which is an innate immune agonist, to TMEV-infected mice during the innate immune response resulted in decreased myelin-specific CD4(+) T cell responses and reduced demyelinating disease. These results demonstrate that activating or enhancing the innate immune response can reduce the subsequent initiation and progression of the autoimmune response and demyelinating disease.
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PMID:The innate immune response affects the development of the autoimmune response in Theiler's virus-induced demyelinating disease. 1938 Aug 18

The effects of controlled release on immune response to an immunomodulating peptide were evaluated in a murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). The peptide, Ac-PLP-BPI-NH(2)-2 (Ac-HSLGKWLGHPDKF-(AcpGAcpGAcp)(2)-ITDGEATDSG-NH(2); Ac = acetyl, Acp = epsilon aminocaproic acid) was designed to suppress T-cell activation in response to PLP(139-151), an antigenic peptide in MS. Poly-lactide-co-glycolide (PLGA) microparticles containing Ac-PLP-BPI-NH(2)-2 (8+/-4 microm, 1.4+/-0.2% (w/w)) were prepared by a powder-in oil-in water emulsion-solvent evaporation method, sterilized and administered subcutaneously (s.c.) to SJL/J (H-2(s)) mice in which EAE had been induced by immunization with PLP(139-151). Treatment groups received Ac-PLP-BPI-NH(2)-2: (i) in solution by repeated i.v. or s.c. injection, (ii) in solution co-administered with blank PLGA microparticles, (iii) in solution co-administered with Ac-PLP-BPI-NH(2)-2 loaded microparticles, and (iv) as Ac-PLP-BPI-NH(2)-2 loaded microparticles. Administration of Ac-PLP-BPI-NH(2)-2 as an s.c. solution produced clinical scores and maintenance of body weight comparable to i.v. solution, but with reduced overall survival, presumably due to anaphylaxis. Administration as s.c. microparticles provided a somewhat less effective reduction in symptoms but with no toxicity during treatment. Thus, the results suggest that s.c. administration of Ac-PLP-BPI-NH(2)-2 microparticles can provide pharmacological efficacy and reduction in dosing frequency without increased toxicity.
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PMID:Immune response to controlled release of immunomodulating peptides in a murine experimental autoimmune encephalomyelitis (EAE) model. 1974 37

MBP-PLP fusion protein (MP4)-induced experimental autoimmune encephalomyelitis (EAE) is a model for multiple sclerosis (MS) that encompasses both a time-dependent attack on central nervous system (CNS) regions and a B cell component, mirroring important features of human multiple sclerosis. Comparing C57BL/6 with B6.129 mice immunized with MP4, we point out similarities regarding these hallmarks and thus propose that they are largely dependent on the nature of the MP4 antigen itself, while differences between the two strains suggest that additional fine-tuning is brought about by the genetic repertoire of the animal. Overall, our data imply that (i) the interplay between both the antigenic trigger and genetic variables can define the outcome of MP4-induced autoimmune encephalomyelitis in C57BL/6 and B6.129 mice and (ii) that MP4 is not only a strong neuroantigen when it comes to reproducing the dynamics in effector mechanisms as is typical of the disease but also a promising agent for studying interindividual heterogeneity derived from genetic diversity in EAE/MS.
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PMID:Delineating the impact of neuroantigen vs genetic diversity on MP4-induced EAE of C57BL/6 and B6.129 mice. 2007 58


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