Mannosylation of mutated MBP83–99 peptides diverts immune responses from Th1 to Th2

Katsara, Maria; Yuriev, Elizabeth; Ramsland, Paul A.; Deraos, George; Tselios, Theodore; Matsoukas, John; Apostolopoulos, Vasso

doi:10.1016/j.molimm.2008.04.024

Cited by 34 publications

(66 citation statements)

References 52 publications

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“…It was found that these peptides-mannan conjugations induce T cell responses with the induction of high level of IL-4 while only the MBP 83-99 (Phe 91 ) peptide generated IFN-c secreting T cells. Moreover, high antibody levels were induced by MBP 83-99 (Tyr 91 ) and low by MBP 83-99 (Phe 91 ) peptides [17]. A very significant observation is that these peptides did not cross-react with native MBP protein at 1/200 and 1/1,600 sera dilution [17].…”

Section: Introductionmentioning

confidence: 93%

“…However, the linear peptides resulted in non-cross reactivity by T-cells against native MBP 83-99 epitope [16]. Furthermore, the linear MBP 83-99 (Phe 91 ) and MBP 83-99 (Tyr 91 ) peptide analogues conjugated to reduced mannan were immunized in SJL/J mice [17]. It was found that these peptides-mannan conjugations induce T cell responses with the induction of high level of IL-4 while only the MBP 83-99 (Phe 91 ) peptide generated IFN-c secreting T cells.…”

Section: Introductionmentioning

confidence: 99%

“…A very significant observation is that these peptides did not cross-react with native MBP protein at 1/200 and 1/1,600 sera dilution [17]. The MBP 83-99 (Tyr 91 ) peptide on reduced mannan gave the best cytokine and antibody profile and constitutes a promising candidate peptide for the immunotherapy of Multiple Sclerosis (MS) [17,18].…”

Section: Introductionmentioning

confidence: 99%

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Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Potamitis

Matsoukas

Tselios

et al. 2011

J Comput Aided Mol Des

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The two new synthetic analogues of the MBP(83-99) epitope substituted at Lys(91) (primary TCR contact) with Phe [MBP(83-99) (Phe(91))] or Tyr [MBP(83-99) (Tyr(91))], have been structurally elucidated using 1D and 2D high resolution NMR studies. The conformational analysis of the two altered peptide ligands (APLs) has been performed and showed that they adopt a linear and extended conformation which is in agreement with the structural requirements of the peptides that interact with the HLA-DR2 and TCR receptors. In addition, Molecular Dynamics (MD) simulations of the two analogues in complex with HLA-DR2 (DRA, DRB1*1501) and TCR were performed. Similarities and differences of the binding motif of the two analogues were observed which provide a possible explanation of their biological activity. Their differences in the binding mode in comparison with the MBP(83-99) epitope may also explain their antagonistic versus agonistic activity. The obtained results clearly indicate that substitutions in crucial amino acids (TCR contacts) in combination with the specific conformational characteristics of the MBP(83-99) immunodominant epitope lead to an alteration of their biological activity. These results make the rational drug design intriguing since the biological activity is very sensitive to the substitution and conformation of the mutated MBP epitopes.

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Potamitis

Matsoukas

Tselios

et al. 2011

J Comput Aided Mol Des

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“…In recent studies by our group, mannosylation of mutated human MBP83-99 peptides gave promising results because they diverted the immune responses from Th1 to Th2 in SJL/J mice and generated antibodies which did not cross react with the native MBP protein. In addition, conjugated peptides MBP83-99[Y91] and MBP83-99[F91] gave the best cytokine and antibody profile constituting promising candidate peptides for immunotherapy of MS [20,22].…”

Section: T-cell Clone Created In Vitro From T-cells Isolated From An mentioning

confidence: 99%

Properties of myelin altered peptide ligand cyclo(87-99)(Ala91,Ala96)MBP87-99 render it a promising drug lead for immunotherapy of multiple sclerosis

Deraos

Rodi

Kalbacher

et al. 2015

European Journal of Medicinal Chemistry

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“…Recently, the I-A s structure was deduced from the crystal structure of I-A u and a binding motif suffested. 52,53 MHC class II molecule is a noncovalently bonded heterodimer composed of α and b chains (α 1 , α 2 , b 1 and b 2 ) (Fig. 1).…”

Section: Mhc Class II Moleculesmentioning

confidence: 99%

MHC and MHC‑like molecules: Structural perspectives on the design of molecular vaccines

Apostolopoulos¹,

Yuriev²,

Lazoura³

et al. 2008

Human Vaccines

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© 2 0 0 8 L A N D E S B I O S C I E N C E . D O N O T D I S T R I B U T E .peptide-binding proteins as well as antigen processing molecules, such as TAP and tapasin. The MHC class II locus encodes heterodimeric peptide-binding proteins and proteins that modulate peptide loading onto MHC class II proteins in the lysosomal compartment, such as MHC class II DM, -DQ and -DP. MHC class I proteins are expressed on all nucleated cells and MHC class II are found on only a few specialized cell types; B-cells, neutrophils, dendritic cells and thymic epithelial cells and can be induced on macrophages and human T cells. The MHC class III locus encodes for other immune components, i.e., complement components (C2, C4, factor B), cytokines (TNFα and TNFb) and HSP70. Stimulation of CD8 T CellsMHC, first described more than 70 years ago to control transplant rejection in mice, was initially termed H-2. There are three gene families for murine MHC class I: H-2K, H-2D and H-2L and for human MHC: HLA-A, HLA-B and HLA-C. The first step in CD8 + T cell generation is the uptake and presentation of peptides by antigen presenting cells through their MHC molecules. Peptides bound to MHC class I are usually endogenous and cytosolic although exogenous peptides may also be presented by MHC class I molecules. 4,5 Exogenous antigens are taken up by antigen presenting cells (APCs), primarily dendritic cells, into phagosomes and early and late endosomes and presented to MHC class II molecules. Numerous reports have demonstrated that in early endosomes some antigens can either degrade or escape out of the endosome into the cytosol and enter the proteasome. 4,5 Likewise, endogenous peptides are primarily generated in the cytosol by the proteasome. From this point, exogenous-and endogenous-derived peptides follow the same pathway. The proteasome consists of 24 subunits, half of which contain proteolytic activity. The proteasome degrades antigens (proteins) into small peptides which are released into the cytosol. The peptides are transported from the cytosol into the endoplasmic reticulum (ER) via the transporter associated with antigen processing (TAP1 and TAP2) by ATP. In the ER, peptides bind to the newly synthesized MHC class I molecules following the formation of a large multimeric complex which involves TAP, tapasin, calreticulin, calnexin and ER60. From the ER, the peptide-MHC class I complex is transported to the surface of APCs through the secretory pathway (Golgi) where the complex undergoes several posttranslational modifications. Then the peptide-MHC class I complexes expressed

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Mannosylation of mutated MBP83–99 peptides diverts immune responses from Th1 to Th2

Cited by 34 publications

References 52 publications

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Properties of myelin altered peptide ligand cyclo(87-99)(Ala91,Ala96)MBP87-99 render it a promising drug lead for immunotherapy of multiple sclerosis

MHC and MHC‑like molecules: Structural perspectives on the design of molecular vaccines

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