In:
Immunotherapy, Future Medicine Ltd, Vol. 6, No. 6 ( 2014-06), p. 709-724
Abstract:
Background: The predominant proteins of the CNS are myelin basic protein, proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein. PLP 139-151 is one of the major encephalitogenic epitopes of PLP. The epitope PLP 139-151 binds to MHC class II (I-A s ) of SJL/J mice and induces Th1 responses. Aim: The aim was to synthesize and test the immunological activity and cyclic analogs of PLP 139-151 peptide and determine the immunological differences between adjuvant and conjugation to mannan. Materials & methods: We designed and synthesized cyclic peptides based on the linear PLP 139-151 epitope by mutating critical T-cell receptor contact sites of residues W 144 and H 147 , resulting in the mutant peptides PLP 139-151 , [L 144 , R 147 ]PLP 139-151 or cyclo(139-151)PLP 139-151 and cyclo(139-151) [L 144 , R 147 ]PLP 139-151 . In this study, mice were immunized with mutant peptides either emulsified in complete Freund's adjuvant or conjugated to reduced mannan and responses were assessed. Results: Linear double-mutant peptide [L 144 , R 147 ]PLP 139-151 induced high levels of IL-4 responses and low levels of IgG total, and cyclization of this analog elicited low levels of IFN-γ. Moreover, linear [L 144 , R 147 ]PLP 139-151 conjugated to reduced mannan did not induce IFN-γ, whilst both linear agonist PLP 139-151 and cyclic agonist cyclo(139-151)PLP 139-151 induced IFN-γ-secreting T cells. Molecular dynamics simulations of linear and cyclic(139-151)PLP 139-151 analogs indicated the difference in topology of the most important for biological activity amino acids. Conclusion: Cyclic double-mutant analog cyclo(139-151) [L 144 , R 147 ]PLP 139-151 has potential for further studies for the immunotherapy of multiple sclerosis.
Type of Medium:
Online Resource
ISSN:
1750-743X
,
1750-7448
Language:
English
Publisher:
Future Medicine Ltd
Publication Date:
2014
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