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.
Katsara
Maria
M
Burnet Institute (Austin Campus), Immunology and Vaccine Laboratory, Studley Road, Heidelberg, 3084 Victoria, Australia.
Yuriev
Elizabeth
E
Ramsland
Paul A
PA
Deraos
George
G
Tselios
Theodore
T
Matsoukas
John
J
Apostolopoulos
Vasso
V
D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation / Q000502:physiology*; D004676:Myelin Basic Protein / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
D004676:Myelin Basic Protein; D010446:Peptide Fragments; C104448:myelin basic protein 83-99; D015847:Interleukin-4; D007371:Interferon-gamma