Altered peptide ligands of myelin basic protein ( MBP87-99 ) conjugated to reduced mannan modulate immune responses in mice.
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-gamma (IFN-gamma) and interleukin-4 (IL-4) responses compared with only IFN-gamma 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-gamma compared with the native MBP(87-99) peptide. However, [A(91), A(96)]MBP(87-99) conjugated to reduced mannan did not induce IFN-gamma-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.
Katsara
Maria
M
Immunology and Vaccine, and Structural Immunology Laboratories, Burnet Institute, Centre for Immunology, AMREP, Prahran, Vic., Australia.
Yuriev
Elizabeth
E
Ramsland
Paul A
PA
Tselios
Theodore
T
Deraos
George
G
Lourbopoulos
Athanasios
A
Grigoriadis
Nikolaos
N
Matsoukas
John
J
Apostolopoulos
Vasso
V
D000818:Animals; D024201:Bystander Effect / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D005620:Freund's Adjuvant; D007114:Immunization / Q000379:methods; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008024:Ligands; D008351:Mannans / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D009103:Multiple Sclerosis / Q000276:immunology / Q000628:therapy; D009154:Mutation; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D007074:Immunoglobulin G; D008024:Ligands; D008351:Mannans; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C115314:myelin basic protein 87-99; D015847:Interleukin-4; D007371:Interferon-gamma; D005620:Freund's Adjuvant