Peptide 15-mers of defined sequence that substitute for random amino acid copolymers in amelioration of experimental autoimmune encephalomyelitis

Joel N.H. Stern, Zsolt Illés, Jayagopala Reddy, Derin B. Keskin, Masha Fridkis-Hareli, Vijay K. Kuchroo, Jack L. Strominger

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1620-1625
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number5
DOIs
StatePublished - Feb 1 2005

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Autoimmune Experimental Encephalomyelitis
HLA Antigens
Amino Acids
Peptides
T-Lymphocytes
Multiple Sclerosis
Immunodominant Epitopes
Myelin Basic Protein
Adoptive Transfer
Autoantigens
Interleukin-4
Interleukin-10
Interleukin-2
myelin basic protein 85-99
Spleen
Lymph Nodes
Cytokines
Cell Line

Keywords

  • Cop1
  • HLA-DR
  • Multiple sclerosis
  • T cells

ASJC Scopus subject areas

  • General

Cite this

Peptide 15-mers of defined sequence that substitute for random amino acid copolymers in amelioration of experimental autoimmune encephalomyelitis. / Stern, Joel N.H.; Illés, Zsolt; Reddy, Jayagopala; Keskin, Derin B.; Fridkis-Hareli, Masha; Kuchroo, Vijay K.; Strominger, Jack L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 5, 01.02.2005, p. 1620-1625.

Research output: Contribution to journalArticle

Stern, Joel N.H. ; Illés, Zsolt ; Reddy, Jayagopala ; Keskin, Derin B. ; Fridkis-Hareli, Masha ; Kuchroo, Vijay K. ; Strominger, Jack L. / Peptide 15-mers of defined sequence that substitute for random amino acid copolymers in amelioration of experimental autoimmune encephalomyelitis. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 5. pp. 1620-1625.
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AU - Stern, Joel N.H.

AU - Illés, Zsolt

AU - Reddy, Jayagopala

AU - Keskin, Derin B.

AU - Fridkis-Hareli, Masha

AU - Kuchroo, Vijay K.

AU - Strominger, Jack L.

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AB - 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.

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