Immune responses of linear and cyclic PLP139–151 mutant peptides in SJL/J mice: peptides in their free state versus mannan conjugation

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Abstract

Background:

The predominant proteins of the CNS are myelin basic protein, proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein. PLP139–151 is one of the major encephalitogenic epitopes of PLP. The epitope PLP139–151 binds to MHC class II (I-As) of SJL/J mice and induces Th1 responses.

Aim:

The aim was to synthesize and test the immunological activity and cyclic analogs of PLP139–151 peptide and determine the immunological differences between adjuvant and conjugation to mannan.

Materials & methods:

We designed and synthesized cyclic peptides based on the linear PLP139–151 epitope by mutating critical T-cell receptor contact sites of residues W144 and H147, resulting in the mutant peptides PLP139–151, [L144, R147]PLP139–151 or cyclo(139–151)PLP139–151 and cyclo(139–151) [L144, R147]PLP139–151. 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 [L144, R147]PLP139–151 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 [L144, R147]PLP139–151 conjugated to reduced mannan did not induce IFN-γ, whilst both linear agonist PLP139–151 and cyclic agonist cyclo(139–151)PLP139–151 induced IFN-γ-secreting T cells. Molecular dynamics simulations of linear and cyclic(139–151)PLP139–151 analogs indicated the difference in topology of the most important for biological activity amino acids.

Conclusion:

Cyclic double-mutant analog cyclo(139–151) [L144, R147]PLP139–151 has potential for further studies for the immunotherapy of multiple sclerosis.

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