Peptide 15-mers of defined sequence that substitute for random amino acid copolymers in amelioration of experimental autoimmune encephalomyelitis.
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 humanized 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.
Stern
Joel N H
JN
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Illés
Zsolt
Z
Reddy
Jayagopala
J
Keskin
Derin B
DB
Fridkis-Hareli
Masha
M
Kuchroo
Vijay K
VK
Strominger
Jack L
JL
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D015195:Drug Design; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D010455:Peptides