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

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-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 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 W(144) and H(147), resulting in the mutant peptides PLP139-151, [L(144), R(147)]PLP139-151 or cyclo(139-151)PLP139-151 and cyclo(139-151) [L(144), R(147)]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 [L(144), R(147)]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 [L(144), R(147)]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) [L(144), R(147)]PLP139-151 has potential for further studies for the immunotherapy of multiple sclerosis.

• Authors: Maria Katsara, Spyros Deraos, Theodore V Tselios, Geoffrey Pietersz, John Matsoukas, Vasso Apostolopoulos
• Journal: Immunotherapy (Immunotherapy) Vol. 6 Issue 6 Pg. 709-24 ( 2014) ISSN: 1750-7448 [Electronic] England
• PMID: 25186603 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Epitopes
• Immunoglobulin G
• Mannans
• Myelin Proteolipid Protein
• Peptide Fragments
• Peptides
• Peptides, Cyclic
• myelin proteolipid protein (139-151)
• Interleukin-4
• Interferon-gamma

Topics

• Amino Acid Sequence
• Animals
• Encephalomyelitis, Autoimmune, Experimental (immunology)
• Enzyme-Linked Immunosorbent Assay
• Epitopes (chemistry, genetics, immunology)
• Female
• Humans
• Immunity, Cellular (drug effects, immunology)
• Immunization
• Immunoglobulin G (blood, immunology)
• Interferon-gamma (immunology, metabolism)
• Interleukin-4 (immunology, metabolism)
• Mannans (chemistry, immunology)
• Mice, Inbred Strains
• Multiple Sclerosis (immunology)
• Mutation (immunology)
• Myelin Proteolipid Protein (genetics, immunology)
• Peptide Fragments (genetics, immunology)
• Peptides (chemistry, genetics, immunology, pharmacology)
• Peptides, Cyclic (chemistry, genetics, immunology, pharmacology)
• T-Lymphocytes (drug effects, immunology, metabolism)