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Altered peptide ligands of myelin basic protein (MBP 87–99 ) conjugated to reduced mannan modulate immune responses in mice
Author(s) -
Katsara Maria,
Yuriev Elizabeth,
Ramsland Paul A.,
Tselios Theodore,
Deraos George,
Lourbopoulos Athanasios,
Grigoriadis Nikolaos,
Matsoukas John,
Apostolopoulos Vasso
Publication year - 2009
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/j.1365-2567.2009.03137.x
Subject(s) - myelin basic protein , peptide , epitope , major histocompatibility complex , chemistry , immune system , microbiology and biotechnology , biology , antigen , biochemistry , immunology , myelin , endocrinology , central nervous system
Summary Mutations of peptides to generate altered peptide ligands, capable of switching immune responses from T helper 1 (Th1) to T helper 2 (Th2), are promising candidates for the immunotherapy of autoimmune diseases such as multiple sclerosis (MS). We synthesized two mutant peptides from myelin basic protein 87–99 (MBP 87–99 ), an immunodominant peptide epitope identified in MS. Mutations of residues K 91 and P 96 , known to be critical T‐cell receptor (TCR) contact sites, resulted in the mutant peptides [R 91 , A 96 ]MBP 87–99 and [A 91 , A 96 ]MBP 87–99 . Immunization of mice with these altered peptide ligands emulsified in complete Freund’s adjuvant induced both interferon‐γ (IFN‐γ) and interleukin‐4 (IL‐4) responses compared with only IFN‐γ responses induced to the native MBP 87–99 peptide. It was of interest that [R 91 , A 96 ]MBP 87–99 conjugated to reduced mannan induced 70% less IFN‐γ compared with the native MBP 87–99 peptide. However, [A 91 , A 96 ]MBP 87–99 conjugated to reduced mannan did not induce IFN‐γ‐secreting T cells, but elicited very high levels of interleukin‐4 (IL‐4). Furthermore, antibodies generated to [A 91 , A 96 ]MBP 87–99 peptide conjugated to reduced mannan did not cross‐react with the native MBP 87–99 peptide. By molecular modelling of the mutant peptides in complex with major histocompatibility complex (MHC) class II, I‐A s , novel interactions were noted. It is clear that the double‐mutant peptide analogue [A 91 , A 96 ]MBP 87–99 conjugated to reduced mannan is able to divert immune responses from Th1 to Th2 and is a promising mutant peptide analogue for use in studies investigating potential treatments for MS.