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 [(YMBP83-99)-M-91] 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-A(s). Molecular modeling was used to identify H-bonding and van der Waals interactions between peptides and MHC (I-A(s)). (C) 2008 Elsevier Ltd. All rights reserved