UMLS:C0014070 - FACTA Search

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Query: UMLS:C0014070 (encephalomyelitis)
13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelination after intracerebral inoculation of the virus into susceptible mouse strains. We isolated from a TMEV BeAn 8386 viral stock, a low-pathogenic variant which requires greater than a 10,000-fold increase in viral inoculation for the manifestation of detectable clinical signs. Intracerebral inoculation of this variant virus induced a strong, long-lasting, protective immunity from the demyelinating disease caused by pathogenic TMEV. The levels of antibodies to the whole virus as well as to the major linear epitopes were similar in mice infected with either the variant or wild-type virus. However, persistence of the variant virus in the central nervous system (CNS) of mice was significantly lower than that of the pathogenic virus. In addition, the T-cell response to the predominant VP1 (VP1(233-250)) epitope in mice infected with the variant virus was significantly weaker than that in mice infected with the parent virus, while similar T-cell responses were induced against another predominant epitope (VP2(74-86)). Further analyses indicated that a change of lysine to arginine at position 244 of VP1, which is the only amino acid difference in the P1 region, is responsible for such differential T-cell recognition. Thus, the difference in the T-cell reactivity to this VP1 region as well as the low level of viral persistence in the CNS may account for the low pathogenicity of this spontaneous variant virus.
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PMID:A spontaneous low-pathogenic variant of Theiler's virus contains an amino acid substitution within the predominant VP1(233-250) T-cell epitope. 944 95

The NH2-terminal peptide of myelin basic protein (MBP) bound to the class II major histocompatibility complex (MHC) protein I-Au is an immunodominant epitope in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. However, the MBP-I-Au complex is very unstable. To investigate this, we performed site-directed mutagenesis of the I-Au MHC protein and the MBP peptide. Biochemical, T cell activation, and molecular modeling studies of mutant complexes demonstrate that the MBP peptide's key residue for MHC binding, lysine 4, is buried in the P6 pocket of I-Au, which is predominantly hydrophobic. This implies that the MBP-I-Au complex differs from more stable complexes in two respects: (a) the peptide leaves the NH2-terminal region of the MHC peptide-binding cleft unoccupied; (b) the peptide is not anchored by typical favorable interactions between peptide side chains and MHC pockets. To test these hypotheses, a modified MBP peptide was designed based on molecular modeling, with the aim of producing strong I-Au binding. Extension of the NH2 terminus of MBP with six amino acids from the ova peptide, and replacement of the lysine side chain in the P6 pocket with an aromatic anchor, results in >1,000-fold increased binding stability. These results provide an explanation for the unusual peptide-MHC-binding kinetics of MBP, and should facilitate an understanding of why mice are not tolerant to this self-peptide- MHC complex.
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PMID:Evidence that the autoimmune antigen myelin basic protein (MBP) Ac1-9 binds towards one end of the major histocompatibility complex (MHC) cleft. 956 42

Copolymer 1 (Cop 1) is a random synthetic amino acid copolymer of L-alanine, L-glutamic acid, L-lysine, and L-tyrosine, effective both in suppression of experimental allergic encephalomyelitis and in the treatment of relapsing forms of multiple sclerosis. Cop 1 binds promiscuously and very efficiently to living APCs of various HLA haplotypes. In the present study, a substantial part of the whole mixture of random polypeptides that compose Cop 1 was shown to bind to purified human HLA-DR1, DR2, and DR4 with high affinity in a temperature- and time (and, in the case of DR4, pH)-dependent manner, and was competitively inhibited by DR-restricted peptides, but not by peptide derivatives that bind with low affinity. Bacterial superantigens inhibited Cop 1 binding only at very high concentrations. The formation of the Cop 1-DR1 complex was also shown by SDS-PAGE. These findings represent the first direct evidence for interactions of Cop 1 with purified DR molecules, and suggest that its effectiveness in experimental allergic encephalomyelitis and multiple sclerosis may be directly related to its binding in the groove of HLA-DR proteins.
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PMID:Promiscuous binding of synthetic copolymer 1 to purified HLA-DR molecules. 957 43

Copolymer 1 [poly(Y,E,A,K)] is a random synthetic amino acid copolymer of L-tyrosine, L-glutamic acid, L-alanine, and L-lysine that is effective both in suppression of experimental allergic encephalomyelitis and in the treatment of relapsing forms of multiple sclerosis. Copolymer 1 binds promiscuously and very efficiently to purified HLA-DR molecules within the peptide-binding groove. In the present study, YEAK and YEAK-related copolymers and type II collagen (CII) peptide 261-273, a candidate autoantigen in rheumatoid arthritis (RA), competed for binding to RA-associated HLA-DR molecules encoded by DRB1*0101 and DRB1*0401. Moreover, these copolymers (particularly YEAK, YAK, and YEK) inhibited the response of DR1- and DR4-restricted T cell clones to the CII epitope 261-273 by >50%. This direct evidence both for competitive interactions of these copolymers and CII peptide with RA-associated HLA-DR molecules and for inhibition of CII-specific T cell responses suggests that these compounds should be evaluated in animal models for rheumatoid arthritis.
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PMID:Synthetic amino acid copolymers that bind to HLA-DR proteins and inhibit type II collagen-reactive T cell clones. 977 May 19

The N-terminal peptide Ac1-11 of myelin basic protein induces experimental autoimmune encephalomyelitis in H-2(u) and (H-2(u) x H-2(s)) mice but does not in H-2(s) mice. Ac1-11 binds weakly to the class II major histocompatibility complex (MHC) molecule I-Au but not at all to I-As. We have studied the interaction of Ac1-11 and I-Au as a model system for therapeutic intervention in the autoimmune response seen in experimental autoimmune encephalomyelitis. Two polymorphic residues that differ between I-Au and I-As, Y26beta and T28beta, and one conserved residue, E74beta, confer specific binding of Ac1-11 to I-Au. A fourth residue, R70beta in I-Au, affects both peptide binding and T cell recognition. These results are consistent with a model that places arginine at position five of Ac1-11 in pockets 4 and 7 of the MHC groove, which is formed in part by residues 26, 28, 70, and 74 of Abetau and places lysine at position four of Ac1-11, previously shown to be a major MHC contact, in hydrophobic pocket 6. The data indicate that the primary region of I-Au that confers specific binding of Ac1-11 lies in the center of the peptide binding groove rather than in the region that contacts the N terminus of the peptide, as has been shown for HLA DR and the homologous I-E molecules.
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PMID:A small number of residues in the class II molecule I-Au confer the ability to bind the myelin basic protein peptide Ac1-11. 987 95

Chronic experimental allergic encephalomyelitis (CEAE) is an established experimental model for multiple sclerosis (MS). The demyelinating lesions in the white matter of the central nervous system observed in CEAE and in MS are accompanied by various neurophysiological alterations. Among the best defined electrophysiological abnormalities are the changes in event-related potentials, in particular evoked potentials involving the spinal cord, i.e. motor and sensory evoked potentials. Less familiar are the changes observed in the electroencephalogram of CEAE-affected animals, which are also encountered in the human equivalent, MS. In the present experiment we evaluated the therapeutic value of a neurotrophic peptide treatment [H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH, an ACTH4-9 analogue] and its effect on the delayed flash visual evoked potentials (VEP) and power spectra of the electroencephalogram, during a 17-week follow-up of CEAE. CEAE animals treated with the neurotrophic peptide were protected against the development of neurological symptoms during the course of the demyelinating syndrome. VEPs of animals suffering from CEAE showed a delay of the latencies of the late components which was significantly counteracted by peptide treatment. The peak-to-peak amplitude of the VEP afterdischarge recorded from CEAE animals was significantly increased during the course of CEAE and correlated closely with the progression of the myelinopathy. Furthermore, CEAE animals showed an increase of electroencephalogram (EEG) beta activity of up to 500% as compared with the age-matched control group. This increase in beta power mainly consisted of a prevailing 20-21 Hz peak, a frequency that normally is not dominant in control EEG recordings of the rat during passive wakefulness. All these electrophysiological phenomena were absent in ACTH4-9 analogue-treated animals. The present findings underscore the potential importance of a neurotrophic peptide treatment in the pharmacotherapy of central demyelinating syndromes, and possibly of MS.
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PMID:Neurotrophic ACTH4-9 analogue therapy normalizes electroencephalographic alterations in chronic experimental allergic encephalomyelitis. 987 50

Experimental allergic encephalomyelitis (EAE) is induced in susceptible animals by immunodominant determinants of myelin basic protein (MBP), such as guinea pig sequence MBP72-85. Two linear and one cyclic analogues based on MBP72-85 have been synthesized and evaluated for EAE induction in Lewis rats. The linear peptide Gln1-Lys2-Ser3-Gln4-Arg5-Ser6-Gln7-+ ++Asp8-Glu9-Asn10-Pro11-Val12 (1) was found to induce EAE, while substitution of the Asp residue at position 8 with Ala resulted in an analogue (2) which suppressed the induction of EAE by its parent peptide. Nuclear magnetic resonance studies of analogue 1 in dimethyl sulfoxide (DMSO) using TOCSY/ROESY techniques revealed a head-to-tail intramolecular interaction (ROE connectivity between betaVal12-gammaGln1), indicating a pseudocyclic conformation for the immunogenic peptide 1. A conformational model was developed using NMR constraints and molecular dynamics. Based on this model, a novel amide-linked cyclic analogue has been designed and synthesized by connecting the side-chain amino and carboxyl groups of Lys and Glu at positions 2 and 9, respectively, of linear analogue 1. The cyclic analogue (3) had similar activity to the linear peptide 1, and the EAE effects induced by cyclic analogue 3 were completely suppressed by co-injection with the Ala81-substituted analogue 2 in Lewis rats. The similar potencies of analogues 1 and 3 support the proposed cyclic comformation suggested for analogue 1 from NMR studies and computer modeling and provides the basis for designing more potent molecules with improved properties such as increased resistance to degradation.15 The present findings suggest that a cyclic conformation for the MBP72-85 epitope positions the carboxyl group of Asp81 correctly and presumably other side groups of the peptide such as Arg78 in a manner which enables functional binding of the trimolecular complex MHC-peptide-T cell receptor resulting in EAE.
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PMID:Design and synthesis of a potent cyclic analogue of the myelin basic protein epitope MBP72-85: importance of the Ala81 carboxyl group and of a cyclic conformation for induction of experimental allergic encephalomyelitis. 1019 61

Copolymer 1 [Cop 1, poly(Y,E,A,K)] is a random synthetic amino acid copolymer of L-tyrosine, L-glutamic acid, L-alanine and L-lysine, effective both in suppression of experimental allergic encephalomyelitis and in the treatment of relapsing forms of multiple sclerosis. Cop 1 binds promiscuously and very efficiently to purified human HLA-DR molecules within the peptide-binding groove. In the present study the binding of copolymers composed of three of the four amino acids found in poly(Y,E,A,K) to purified class II MHC molecules was examined. Poly(Y,A,K) and poly(Y,E,A,K) bound to purified human HLA-DR1 or -DR4 molecules with affinity higher than poly(Y,E,A), poly(E,A,K) or poly(Y,E,K), whereas poly(Y,E,A,K) and poly(E,A,K) were the better binders of HLA-DR2 molecules. On the other hand, poly(Y,E,A) and poly(Y,A,K) inhibited the binding of biotinylated poly(Y,E,A,K) to these molecules 10-fold more efficiently than poly(Y,E,K). Finally, poly(Y,E,A), poly(Y,A,K) and poly(E,A,K) were cross-reactive with poly(Y,E,A,K) using YEAK-specific T cell lines and clones of mouse or human origin.
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PMID:Binding of random copolymers of three amino acids to class II MHC molecules. 1033 Feb 69

Copolymer 1 (COP), a standardized mixture of synthetic polypeptides consisting of l-glutamic acid, l-lysine, l-alanine, and l-tyrosine, has beneficial effects in multiple sclerosis and experimental autoimmune encephalomyelitis. We selected a panel of 721 COP-reactive T cell lines (TCL) from the blood of COP-treated and untreated multiple sclerosis patients and from healthy donors by using the split-well cloning technique. All TCL selected with COP proliferated in response to COP but not to myelin basic protein (MBP). Conversely, 31 control TCL selected with MBP proliferated in response to MBP but not to COP. We used intracellular double-immunofluorescence flow cytometry for quantitative analysis of cytokine production (IL-4, IFN-gamma) by the TCL. The majority of the COP-reactive TCL from untreated multiple sclerosis patients and normal donors predominantly produced IFN-gamma and, accordingly, were classified as T helper 1 cells (TH1). In contrast, the majority of the COP-reactive TCL from COP-treated patients predominantly (but not exclusively) produced IL-4-i.e., were TH2 (P < 0.05 as assessed by using a suitable preference intensity index). Longitudinal analyses revealed that the cytokine profile of COP-reactive TCL tends to shift from TH1 to TH2 during treatment. Interestingly, although there was no proliferative cross-reaction, about 10% of the COP-reactive TCL responded to MBP by secretion of small amounts of IL-4 or IFN-gamma, depending on the cytokine profile of the TCL. These results are consistent with a protective effect of COP-reactive TH2 cells. It is hypothesized that these cells are activated by COP in the periphery, migrate into the central nervous system, and produce immunomodulatory cytokines after local recognition of MBP.
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PMID:Multiple sclerosis: comparison of copolymer-1- reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells. 1086 Oct 11

Additional structure-activity relationship studies on potent cyclic peptide inhibitors of very late antigen-4 (VLA-4) are reported. The new N- to C-terminal cyclic hexa-, hepta- and octapeptide inhibitors like cyclo(MeIle/MePhe-Leu-Asp-Val-X) (X = 2-4 amino acids containing hydrophobic and/or basic side chains) were synthesized using solid phase peptide synthesis methods. The peptides were evaluated in in vitro cell adhesion assays and in in vivo inflammation models. Many of the peptides like cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) (17), cyclo(MeIle-Leu-Asp-Val-D-Arg-D-Arg-D-Phe) (20), cyclo(MeIle-Leu-Asp-Val-D-Arg-D-Arg-MePhe) (21) and cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg-D-Ala-D-Ala) (23) were potent inhibitors of VLA-4-mediated cell adhesion and inhibited ovalbumin-induced delayed type hypersensitivity (DTH) response in mice. The more potent compounds were highly selective and did not affect U937 cell adhesion to fibronectin (VLA-5), phorbolmyristate acetate or PMA-differentiated U937 cell adhesion to intercellular cell adhesion molecule-1 (ICAM-1)-expressing Chinese hamster ovary cells (LFA-1) and adenosine diphosphate (ADP)-induced platelet aggregation (GPIIb/IIIa). In contrast to the inhibitors like Ac-cyclo(D-Lys-D-Ile-Leu-Asp-Val) and cyclo(CH2CO-Ile-Leu-Asp-Val-Pip-CH2CO-Ile-Leu-Asp-Val-Pip) described earlier, the new compounds were much more compatible with the depot formulations based on poly(DL-lactide-co-glycolide) polymers. The hexapeptide cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) (17) inhibited MOLT-4 cell adhesion to fibronectin and vascular cell adhesion molecule-1 (VCAM-1) with IC50 values of 260 and 330 nM, respectively, and did not show any significant effect against other integrins (IC50 > 300 microM). ZD7349 inhibited ovalbumin-induced DTH response in mice when administered continuously using a mini-pump (ED50 0.01 mg/kg/day) or when given as an s.c. or i.v. bolus injection at a dose of 1-10 mg/kg. ZD7349 was also active in type II collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) tests at a dose of 3-10 mg/kg. The peptide was released from some formulations over a period of 10-20 days. ZD7349 is currently undergoing pre-clinical investigation.
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PMID:Potent cyclic peptide inhibitors of VLA-4 (alpha4beta1 integrin)-mediated cell adhesion. Discovery of compounds like cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) compatible with depot formulation. 1096 69

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