A double mutation of MBP83-99 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 MBP83-99 peptide epitope. Immunization of SJL/J truce with MBP83-99 and mutant [A(91)]MBP83-99, [E-91]MBP83-99, [F-91]MBP83-99, [Y-91]MBP83-99, and [R-91 A(96)] MBP83-99 peptides, induced IFN-gamma, and only [R-91, A(96)] 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 [Y-91]MBP83-99 and [R-91, A(96)]MBP83-99. The double mutant [R-91, A(96)]MBP83-99 was able to antagonize IFN-gamma production in vitro by T cells against the native MBP83-99 peptide. Antibodies generated to [R-91, A(96)]MBP83-99 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)]MBP83-99 double mutant peptide analog is the most prornising for further therapeutic studies. (c) 2008 Elsevier B.V All rights reserved.