Mannosylation of mutated MBP83-99 peptides diverts immune responses from Th1 to Th2.
Multiple sclerosis (MS) is an autoimmune demyelinating disease mediated primarily by CD4+ T cells. The design of peptide mutants of disease-associated myelin epitopes to alter immune responses offers a promising avenue for the treatment of MS. We designed and synthesized a number of peptide analogs by mutating the principal TCR contact residue based on MBP83-99 epitope and these peptides were conjugated to reduced mannan. Immune responses were diverted from Th1 to Th2 in SJL/J mice and generated antibodies which did not cross-react with native MBP protein. Peptide [Y91]MBP83-99 gave the best cytokine and antibody profile and constitutes a promising candidate peptide for immunotherapy of MS. Structural alignment of existing crystal structures revealed the peptide binding motif of I-As. Molecular modeling was used to identify H-bonding and van der Waals interactions between peptides and MHC (I-A(s)).
Katsara
Maria
M
Immunology and Vaccine Laboratory, Burnet Institute (Austin campus), VIC, Australia.
Yuriev
Elizabeth
E
Ramsland
Paul A
PA
Deraos
George
G
Tselios
Theodore
T
Matsoukas
John
J
Apostolopoulos
Vasso
V
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003429:Cross Reactions / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D005260:Female; D008213:Lymphocyte Activation / Q000276:immunology*; D008351:Mannans / Q000276:immunology; D008358:Mannose / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D050505:Mutant Proteins / Q000276:immunology / Q000378:metabolism; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D008351:Mannans; D050505:Mutant Proteins; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C104448:myelin basic protein 83-99; D008358:Mannose