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)

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory and demyelinating disease of the central nervous system and is an animal model of multiple sclerosis (MS). In the present report, a linear analogue and a series of cyclic semi-mimetic peptides were designed and synthesized based on the human myelin basic protein (MBP(87-99)) epitope (Val87-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro-Arg-Thr-Pro90) and on Copolymer I (a mixture of random polymers of Ala, Gln, Lys and Tyr used to treat MS). These analogues were designed looking for suppressors of EAE induced by guinea pig MBP(72-85) epitope (Gln-Lys-Ser-Gln-Arg-Ser-Gln-Asp-Glu-Asn-Pro-Val) in Lewis rats. The linear analogue [Arg91,Ala96]MBP(87-99), in which Arg substitutes Lys91 and Ala substitutes Pro96, was found to be a strong inhibitor which when administered to Lewis rats together with the encephalitogenic agonist MBP(72-85) completely prevented the induction of EAE. In contrast, three N- and C-termini amide-linked cyclic semi-mimetic peptides, [cyclo-Phe-Arg-Asn-Ile-Val-Thr-Ala-Acp (1), cyclo-Phe-Ala-Arg-Gln-Acp (2), cyclo-Tyr-Ala-Lys-Gln-Acp (3)] as well as a Lys side chain and C-terminous cyclic semi mimetic peptide cyclo(Lys, Acp)-Phe-Lys-Asn-Ile-Val-Thr-Ala-Acp (4) which contain segments of MBP(87-99) or are constituted from immunophoric residues of copolymer 1, were ineffective in inducing or inhibiting EAE in Lewis rats. However co-injection of cyclic analogues with MBP(72-85) delayed the onset of EAE indicating a modulatory effect on the EAE activity of MBP(72-85). These findings suggest that molecule length, size of cyclic moiety and backbone conformation are important elements for immunogenic activity. Moreover blockade of MBP(72-85) induced EAE by the unrelated peptide [Arg91,Ala56]MBP(87-99) could indicate that the mechanism of inhibition is not due to binding competition but rather due to the delivery of a negative signal by the antagonist which overcomes the agonist response possibly through the activation of antigen specific regulatory T cells.
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PMID:Treatment of experimental allergic encephalomyelitis (EAE) induced by guinea pig myelin basic protein epitope 72-85 with a human MBP(87-99) analogue and effects of cyclic peptides. 1100 34

CD26 or dipeptidyl peptidase IV (DP IV) is expressed on various cell types, including T cells. Although T cells can receive activating signals via CD26, the physiological role of CD26/DP IV is largely unknown. We used the reversible DP IV inhibitor Lys[Z(NO(2))]-pyrrolidide (I40) to dissect the role of DP IV in experimental autoimmune encephalomyelitis (EAE) and to explore the therapeutic potential of DP IV inhibition for autoimmunity. I40 administration in vivo decreased and delayed clinical and neuropathological signs of adoptive transfer EAE. I40 blocked DP IV activity in vivo and increased the secretion of the immunosuppressive cytokine TGF-beta1 in spinal cord tissue and plasma during acute EAE. In vitro, while suppressing autoreactive T cell proliferation and TNF-alpha production, I40 consistently up-regulated TGF-beta1 secretion. A neutralizing anti-TGF-beta1 Ab blocked the inhibitory effect of I40 on T cell proliferation to myelin Ag. DP IV inhibition in vivo was not generally immunosuppressive, neither eliminating encephalitogenic T cells nor inhibiting T cell priming. These data suggest that DP IV inhibition represents a novel and specific therapeutic approach protecting from autoimmune disease by a mechanism that includes an active TGF-beta1-mediated antiinflammatory effect at the site of pathology.
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PMID:Targeting dipeptidyl peptidase IV (CD26) suppresses autoimmune encephalomyelitis and up-regulates TGF-beta 1 secretion in vivo. 1116 Feb 54

The MHC class II molecule H2-A(s), expressed in the SJL mouse strain, is the principle restriction element of autoreactive CD4(+) T cells mediating experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. We deduced the H2-A(s) ligand motif from the analysis of naturally processed self peptides and from peptide binding studies. Major anchor residues were identified using various sets of substituted and truncated peptides, derived from natural peptide ligands and known H2-A(s) binders like myelin basic protein 81 - 99. The nine-residue H2-A(s) core binding motif comprises an arrangement of anchors in relative positions P1, P4, P6, P7, and P9. The P1 pocket is relatively unspecific and the P6 pocket favors hydrophobic-aliphatic side chains. The P1 pocket contributes little to peptide binding. Primary anchors were identified in P4, P7, and in particular in P9. The preferred anchor residues are Lys (P4), His/Arg (P7), and Pro (P9), respectively. Ala-polysubstituted peptides containing only one of these dominant anchor residues still retain the capacity to bind to H2-A(s). Thus, the presence of only one suitable anchor side chain in P4, P7, or P9 is sufficient for high-affinity peptide binding, at least in the absence of negatively charged side chains nearby. The identified ligand motif facilitates the analysis of immunogenic peptides interacting with H2-A(s) and will allow a better prediction of pathogenetically relevant peptide antigens in the autoimmune mouse model.
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PMID:Ligand motif of the autoimmune disease-associated mouse MHC class II molecule H2-A(s). 1118 Jan 20

T cell-mediated destruction of the myelin sheath causes inflammatory damage of the CNS in multiple sclerosis (MS). The major T and B cell responses in MS patients who are HLA-DR2 (about two-thirds of MS patients) react to a region between residues 84 and 103 of myelin basic protein (1 ). The crystal structure of HLA-DR2 complexed with myelin basic protein(84-102) confirmed that Lys(91) is the major TCR contact site, whereas Phe(90) is a major anchor to MHC and binds the hydrophobic P4 pocket (2 ). We have tested peptides containing repetitive 4-aa sequences designed to bind critical MHC pockets and to interfere with T cell activation. One such sequence, EYYKEYYKEYYK, ameliorates experimental autoimmune encephalomyelitis in Lewis rats, an animal model of MS.
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PMID:Immunomodulation of experimental autoimmune encephalomyelitis with ordered peptides based on MHC-TCR binding motifs. 1150 12

The immunodominant myelin basic protein (MBP) peptide comprising residues 87-99 is a self-antigen in multiple sclerosis (MS). In Lewis rats this epitope induces experimental allergic encephalomyelitis (EAE), a demyelinating disease of the central nervous system, and is a model of MS. Structure-activity studies have shown that Lys(91) and Pro(96) residues are important for encephalitogenicity. Replacement of Lys and/or Pro residues with Arg and/or Ala, respectively, results in suppression of EAE. A potent linear altered peptide ligand of the immunodominant sequence MBP(83-99) has been selected for clinical trial (Nat. Med. 2000, 6, 1167, 1176). In the present report, two cyclic analogues, cyclo(91-99)[Ala(96)]MBP(87-99) and cyclo(87-99)[Arg(91), Ala(96)]MBP(87-99) were designed by NMR and molecular modeling data on human MBP(87-99) epitope (Val(87)-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro-Arg-Thr-Pro(99)) and its linear antagonist peptide analogue [Arg(91), Ala(96)]MBP(87-99). These analogues (altered peptide ligands) inhibited EAE in Lewis rats and decreased inflammation in the spinal cord. In addition, the analogue cyclo(87-99)[Arg(91), Ala(96)]MBP(87-99) induced proliferation of human peripheral blood T-cells. These cyclic MBP(87-99) peptide analogues may lead to the design of potent antagonist mimetics for treating MS.
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PMID:Antagonistic effects of human cyclic MBP(87-99) altered peptide ligands in experimental allergic encephalomyelitis and human T-cell proliferation. 1178 32

Myelencephalon-specific protease (MSP), first identified in the rat and now known to have a human homologue (human kallikrein 6), is preferentially expressed in the central nervous system (CNS), compared with nonneural tissues. MSP has been postulated to have trypsin-like activity, is upregulated in response to glutamate receptor-mediated excitotoxic injury in the CNS, and is downregulated in the brain of Alzheimer's patients. The preferential expression of this enzyme by oligodendrocytes in CNS white matter points to a role in myelin homeostasis. To further characterize the activity and substrate specificity of this newly identified enzyme, we have heterologously expressed MSP in a baculovirus/insect cell line system. We demonstrate that recombinant MSP exhibits a broad specificity for cleavage after arginine but not lysine residues, with kinetic characteristics intermediate between trypsin and pancreatic kallikrein. We show that the pro form of MSP does not self-activate but, rather, requires cleavage after lysine, indicating that mature active MSP is regulated by a distinct protease. MSP may be regulated in part by autolysis, since the active protein is readily inactivated through autolysis at specific internal arginine positions. Additionally, we show that MSP is abundantly expressed in inflammatory cells at sites of demyelination in the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis (MS). In conjunction with data demonstrating the ability of MSP to degrade myelin-associated as well as several extracellular matrix proteins, these findings delineate MSP as a broad-specificity arginine-specific protease with the potential to play a key role in immune-mediated demyelination.
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PMID:Enzymatic properties of rat myelencephalon-specific protease. 1180 15

Theiler's murine encephalomyelitis virus induces immune-mediated demyelination in susceptible mice after intracerebral inoculation. A naturally occurring, low pathogenic Theiler's murine encephalomyelitis virus variant showed a single amino acid change within a predominant Th epitope from lysine to arginine at position 244 of VP1. This substitution is the only one present in the entire viral capsid proteins. In this paper, we demonstrate that the majority of T cells specific for VP1(233-250) and VP2(74-86) from wild-type virus-infected mice are Th1 type and these VP1-specific cells poorly recognize the variant VP1 epitope (VP1(K244R)) containing the substituted arginine. In contrast, the Th2-type T cell population specific for these epitopes predominates in variant virus-infected mice. Immunization with UV-inactivated virus or VP1 epitope peptides could not duplicate the preferential Th1/Th2 responses following viral infection. Interestingly, the major APC populations, such as dendritic cells and macrophages, produce IL-12 on exposure to the pathogenic wild-type virus, whereas they preferentially produce IL-10 in response to the low pathogenic variant virus. Thus, such a spontaneous mutant virus may have a profoundly different capability to induce Th-type responses via selective production of cytokines involved in T cell differentiation and the consequent pathogenicity of virally induced immune-mediated inflammatory diseases.
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PMID:Preferential induction of IL-10 in APC correlates with a switch from Th1 to Th2 response following infection with a low pathogenic variant of Theiler's virus. 1193 84

Glucocorticoid (GC) hormones play a central role in the bidirectional communication between the neuroendocrine and the immune systems and exert, via GC receptors (GR), potent immunosuppressive and anti-inflammatory effects. In this study, we report that GR deficiency of transgenic mice expressing GR antisense RNA from early embryonic life has a dramatic impact in programming the susceptibility to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. GR deficiency renders mice resistant to myelin oligodendrocyte glycoprotein-induced EAE, and such mice do not develop clinical or histological signs of disease compared with EAE-susceptible wild-type mice. Resistance to EAE in GR-deficient mice is associated not with endogenous GC levels, but with a significant reduction in spleen and lymph node cell proliferation. The use of NO inhibitors in vitro indicates that NO is the candidate immunosuppressor molecule. GR-deficient mice develop 3- to 6-fold higher nitrite levels in the periphery and are resistant to NO inhibition by GCs. Specific inhibition of NO production in vivo by treatment with the inducible NO synthase inhibitor, L-N(6)-(1-iminoethyl)-lysine, suppressed circulating nitrites, increased myelin oligodendrocyte glycoprotein-specific cell proliferation, and rendered GR-deficient mice susceptible to EAE. Thus, life-long GR deficiency triggers inducible NO synthase induction and NO generation with consequent down-regulation of effector cell proliferation. These findings identify a novel link among GR, NO, and EAE susceptibility and highlight NO as critical signaling molecule in bidirectional communication between the hypothalamic-pituitary-adrenocortical axis and the immune system.
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PMID:Exposure to a dysfunctional glucocorticoid receptor from early embryonic life programs the resistance to experimental autoimmune encephalomyelitis via nitric oxide-induced immunosuppression. 1202 89

Copolymer 1 (Cop 1, Copaxone [Teva Marion Partners, Kansas City, Missouri, USA]), a random amino acid copolymer of tyrosine (Y), glutamic acid (E), alanine (A), and lysine (K), reduces the frequency of relapses by 30% in relapsing-remitting multiple sclerosis (MS) patients. In the present study, novel random four-amino acid copolymers, whose design was based on the nature of the anchor residues of the immunodominant epitope of myelin basic protein (MBP) 85-99 and of the binding pockets of MS-associated HLA-DR2 (DRB1*1501), have been synthesized by solid-phase chemistry. Poly (Y, F, A, K) (YFAK) inhibited binding of the biotinylated MBP 86-100 epitope to HLA-DR2 molecules more efficiently than did either unlabeled MBP 85-99 or any other copolymer including Cop 1. Moreover, YFAK and poly (F, A, K) (FAK) were much more effective than Cop 1 in inhibition of MBP 85-99-specific HLA-DR2-restricted T cell clones. Most importantly, these novel copolymers suppressed experimental autoimmune encephalomyelitis, induced in the susceptible SJL/J (H-2(s)) strain of mice with the encephalitogenic epitope PLP 139-151, more efficiently than did Cop 1. Thus, random synthetic copolymers designed according to the binding motif of the human immunodominant epitope MBP 85-99 and the binding pockets of HLA-DR2 might be more beneficial than Cop 1 in treatment of MS.
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PMID:Novel synthetic amino acid copolymers that inhibit autoantigen-specific T cell responses and suppress experimental autoimmune encephalomyelitis. 1207 Mar 11

The severity of the experimental autoimmune encephalomyelitis (EAE) induced by peptide myelin oligodendrocyte glycoprotein(35-55)(pMOG(35-55)) is thought to be predominantly influenced by the major histocompatibility complex (MHC), so that C57BL6/J mice, on H2(b) strain, were only mildly sick. However, it remains unclear as to how non-MHC gene regions affect EAE. To determine whether the immunization protocol could have an influence on clinical signs, C57BL6/J mice were immunized with a multiple antigen peptide (MAP) containing eight pMOG(35-55)branches synthesized directly onto a lysine core, myelin oligodendrocyte glycoprotein (35-55)-multiple antigen peptide (MOG(35-55)-MAP), in complete Freund's adjuvant (CFA). In most of the mice, clinical onset (marked weakness) occurred approximately at day 15. All mice injected with MOG(35-55)-MAP had more severe symptoms than those injected with pMOG(35-55), which developed no leg paralysis. All MOG(35-55)-MAP-immunized mice developed EAE symptoms, but 50% had primary-progressive EAE, while the other 50% had relapsing-remitting disease. Leukocyte infiltrations, associated with increased glial fibrillary acidic protein (GFAP) expression by reactive astrocytes, were observed around the lateral ventricles and blood vessels in the brain. Significant positive correlations were established between anti-MOG(35-55)antibody levels and clinical scores or GFAP positivity in the spinal cord. The heterogeneity of EAE progression, observed in these genetically identical individuals, suggests that the environment rather than the genetics plays a role. This observation is highly pertinent as it corresponds to what is seen in clinical MS.
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PMID:Optimization of an animal model of experimental autoimmune encephalomyelitis achieved with a multiple MOG(35-55)peptide in C57BL6/J strain of mice. 1260 12


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