Novel synthetic amino acid copolymers that inhibit autoantigen-specific T cell responses and suppress experimental autoimmune encephalomyelitis.
Copolymer 1 (Cop 1, Copaxone [Teva Marion Partners, Kansas City, Missouri, USA]), a random amino acid copolymer of tyrosine (Y), glutamic acid (E), alanine (A), and lysine (K), reduces the frequency of relapses by 30% in relapsing-remitting multiple sclerosis (MS) patients. In the present study, novel random four-amino acid copolymers, whose design was based on the nature of the anchor residues of the immunodominant epitope of myelin basic protein (MBP) 85-99 and of the binding pockets of MS-associated HLA-DR2 (DRB1*1501), have been synthesized by solid-phase chemistry. Poly (Y, F, A, K) (YFAK) inhibited binding of the biotinylated MBP 86-100 epitope to HLA-DR2 molecules more efficiently than did either unlabeled MBP 85-99 or any other copolymer including Cop 1. Moreover, YFAK and poly (F, A, K) (FAK) were much more effective than Cop 1 in inhibition of MBP 85-99-specific HLA-DR2-restricted T cell clones. Most importantly, these novel copolymers suppressed experimental autoimmune encephalomyelitis, induced in the susceptible SJL/J (H-2(s)) strain of mice with the encephalitogenic epitope PLP 139-151, more efficiently than did Cop 1. Thus, random synthetic copolymers designed according to the binding motif of the human immunodominant epitope MBP 85-99 and the binding pockets of HLA-DR2 might be more beneficial than Cop 1 in treatment of MS.
Fridkis-Hareli
Masha
M
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Santambrogio
Laura
L
Stern
Joel N H
JN
Fugger
Lars
L
Brosnan
Celia
C
Strominger
Jack L
JL
D000595:Amino Acid Sequence; D000596:Amino Acids; D000818:Animals; D001324:Autoantigens / Q000276:immunology* / Q000627:therapeutic use; D002455:Cell Division; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015802:HLA-DR2 Antigen / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000138:chemical synthesis / Q000276:immunology* / Q000627:therapeutic use; D018991:Myelin Proteolipid Protein / Q000276:immunology / Q000627:therapeutic use; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000627:therapeutic use; D011108:Polymers / Q000138:chemical synthesis / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D000596:Amino Acids; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D015802:HLA-DR2 Antigen; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D011108:Polymers; C107908:myelin basic protein 85-99; C435023:myelin proteolipid protein (139-151)