Recognition Pliability Is Coupled to Structural Heterogeneity: A Calmodulin Intrinsically Disordered Binding Region Complex

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

Multiple sclerosis (MS) is an autoimmune demyelinating disease mediated primarily by CD4+ T cells. The design of peptide mutants of disease-associated myelin epitopes to alter immune responses offers a promising avenue for the treatment of MS. We designed and synthesized a number of peptide analogs by mutating the principal TCR contact residue based on MBP83-99 epitope and these peptides were conjugated to reduced mannan. Immune responses were diverted from Th1 to Th2 in SJL/J mice and generated antibodies which did not cross-react with native MBP protein. Peptide [Y91]MBP83-99 gave the best cytokine and antibody profile and constitutes a promising candidate peptide for immunotherapy of MS. Structural alignment of existing crystal structures revealed the peptide binding motif of I-As. Molecular modeling was used to identify H-bonding and van der Waals interactions between peptides and MHC (I-As). © 2008 Elsevier Ltd. All rights reserved

A double mutation of MBP83-99 peptide induces IL-4 responses and antagonizes IFN-? responses

A number of treatment options are available to multiple sclerosis patients, however this needs to be improved. Herein, we designed and synthesized a number of peptides by mutating principal TCR contact residues based on MBP83-99 peptide epitope. Immunization of SJL/J mice with MBP83-99 and mutant [A91]MBP83-99, [E91]MBP83-99, [F91]MBP83-99, [Y91]MBP83-99, and [R91, A96]MBP83-99 peptides, induced IFN-?, and only [R91, A96]MBP83-99 mutant peptide was able to induce IL-4 secretion by T cells. T cells against the native MBP83-99 peptide cross-reacted with all peptides except [Y91]MBP83-99 and [R91,A96]MBP83-99. The double mutant [R91, A96]MBP83-99 was able to antagonize IFN-? production in vitro by T cells against the native MBP83-99 peptide. Antibodies generated to [R91, A96]MBP83-99 did not cross-react with whole MBP protein. Molecular modeling between peptide analogs and H2 I-As demonstrated novel interactions. The [R91, A96]MBP83-99 double mutant peptide analog is the most promising for further therapeutic studies. © 2008 Elsevier B.V. All rights reserved

Treatment of experimental allergic encephalomyelitis (EAE) induced by guinea pig myelin basic protein epitope 72-85 with a human MBP87-99 analogue and effects of cyclic peptides

Journal URL: http://www.sciencedirect.com/science/journal/0968089

Myelin Peptide–Mannan Conjugate Multiple Sclerosis Vaccines: Conjugation Efficacy and Stability of Vaccine Ingredient

Myelin peptide–mannan conjugates have been shown to be potential vaccines in the immunotherapy of multiple sclerosis. The conjugates are comprised from the epitope peptide and the polysaccharide mannan which transfers as a carrier the antigenic peptide to dendritic cells that process and present antigenic peptides at their surface in complex with MHC class I or class II resulting in T-cell stimulation. The conjugation of antigenic peptide with mannan occurs through the linker (Lys–Gly)5, which connects the peptide with the oxidized mannose units of mannan. This study describes novel methods for the quantification of the vaccine ingredient peptide within the conjugate, a prerequisite for approval of clinical trials in the pursuit of multiple sclerosis therapeutics. Myelin peptides, such as MOG35–55, MBP83–99, and PLP131–145 in linear or cyclic form, as altered peptide ligands or conjugated to appropriate carriers, possess immunomodulatory properties in experimental models and are potential candidates for clinical trials