A double mutation of MBP(83-99) peptide induces IL-4 responses and antagonizes IFN-gamma 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 MBP(83-99) peptide epitope. Immunization of SJL/J mice with MBP(83-99) and mutant [A(91)]MBP(83-99), [E(91)]MBP(83-99), [F(91)]MBP(83-99), [Y(91)]MBP(83-99), and [R(91), A(96)]MBP(83-99) peptides, induced IFN-gamma, and only [R(91), A(96)]MBP(83-99) mutant peptide was able to induce IL-4 secretion by T cells. T cells against the native MBP(83-99) peptide cross-reacted with all peptides except [Y(91)]MBP(83-99) and [R(91),A(96)]MBP(83-99). The double mutant [R(91), A(96)]MBP(83-99) was able to antagonize IFN-gamma production in vitro by T cells against the native MBP(83-99) peptide. Antibodies generated to [R(91), A(96)]MBP(83-99) did not cross-react with whole MBP protein. Molecular modeling between peptide analogs and H2 I-A(s) demonstrated novel interactions. The [R(91), A(96)]MBP(83-99) double mutant peptide analog is the most promising for further therapeutic studies.