IMMUNITY TO T-CELL RECEPTOR PEPTIDES IN MULTIPLE-SCLEROSIS - III - PREFERENTIAL IMMUNOGENICITY OF COMPLEMENTARITY-DETERMINING REGION-2 PEPTIDES FROM DISEASE-ASSOCIATED T-CELL RECEPTOR BV GENES

Vaccination with synthetic TCR peptides from the BV5S2 complementarity -determining region 2 (CDR2) can boost significantly the frequency of circulating CD4(+) peptide-specific Th2 cells in multiple sclerosis (M S) patients, with an associated decrease in the frequency of myelin ba sic protein (MBP)-reactive Th1 cells and possible clinical benefit. To evaluate the immunogenicity of CDR2 vs other regions of the TCR, vee vaccinated seven MS patients with overlapping BV5S2 peptides spanning amino acids 1-94. Six patients responded to at least one of three over lapping or substituted CDR2 peptides possessing a core epitope of resi dues 44-52, and one patient also responded to a CDR1 peptide. Of the C DR2 peptides, the substituted (Y49T)BV5S2-38-58 peptide was the most i mmunogenic but cross-reacted with the native sequence and had the stro ngest binding affinity for MS-associated HLA-DR2 alleles, suggesting t hat position 49 is an MHC rather than a TCR contact residue. Two MS pa tients who did not respond to BV5S2 peptides were immunized successful ly with CDR2 peptides from different BV gene families overexpressed by their MBP-specific T cells. Taken together, these results suggest tha t a widely active vaccine for MS might well involve a limited set of s lightly modified CDR2 peptides from BV genes involved in T cell recogn ition of MBP.