A double mutation of MBP83–99 peptide induces IL-4 responses and antagonizes IFN-γ responses

A number of treatment options are available to multiple sclerosis patients, however this needs to be improved. Herein, we designed and synthesized a number of peptides by mutating principal TCR contact residues based on MBP83–99 peptide epitope. Immunization of SJL/J mice with MBP83–99 and mutant [A91]MBP83–99, [E91]MBP83–99, [F91]MBP83–99, [Y91]MBP83–99, and [R91, A96]MBP83–99 peptides, induced IFN-γ, and only [R91, A96]MBP83–99 mutant peptide was able to induce IL-4 secretion by T cells. T cells against the native MBP83–99 peptide cross-reacted with all peptides except [Y91]MBP83–99 and [R91,A96]MBP83–99. The double mutant [R91, A96]MBP83–99 was able to antagonize IFN-γ production in vitro by T cells against the native MBP83–99 peptide. Antibodies generated to [R91, A96]MBP83–99 did not cross-react with whole MBP protein. Molecular modeling between peptide analogs and H2 I-As demonstrated novel interactions. The [R91, A96]MBP83–99 double mutant peptide analog is the most promising for further therapeutic studies.