Veterinary and Biomedical Sciences, Department of

 

Date of this Version

2-1-2005

Document Type

Article

Citation

Proceedings of the National Academy of Sciences (February 1, 2005) 102(5): 1,620-1,625. DOI: 10.1073pnas.0409022102.

Comments

Copyright 2005, PNAS. Used by permission.

Abstract

Myelin basic protein (MBP) is a major candidate autoantigen in multiple sclerosis (MS). Its immunodominant epitope, MBP 85–99, forms a complex with human leukocyte antigen (HLA)-DR2 with which multiple sclerosis is genetically associated. Copolymer 1 (Copaxone), a random amino acid copolymer [poly (Y,E,A,K)n] as well as two modified synthetic copolymers [poly (F,Y,A,K)n and poly (V,W,A,K)n] also form complexes with HLA-DR2 (DRA DRB1*1501) and compete with MBP 85–99 for binding. Moreover, two high-affinity synthetic peptide 15-mers that could inhibit binding even more effectively were previously designed. Here, we show that further-modified peptide 15-mers inhibited even more strongly (in order J5 > J3 > J2) both the binding of MBP 85–99 to HLA-DR2 and IL-2 production by two MBP 85–99-specific HLA-DR2- restricted T cells. J5, J3, and J2 also suppressed both MBP 85–99- induced experimental autoimmune encephalomyelitis (EAE) in hu- manized mice and proteolipid protein 139–151-induced EAE in SJL/J mice. Moreover, none of these previously uncharacterized peptide inhibitors crossreacted with MBP 85–99- or proteolipid protein 139–151-specific T cells. In both cases, spleen and lymph node cultures stimulated with these peptides produced large amounts of Th2 cytokines (IL-4 and IL-10), and adoptive transfer of established T cell lines suppressed disease induction. These peptide 15-mers provide specific, nonrandom sequences that appear to be at least as effective as random copolymers in suppressing EAE in several models.