Arthritis-Associated HLA-DR Molecules Sclerosis- and Rheumatoid Binding Motifs of Copolymer 1 to Multiple

Copolymer 1 (Cop 1, poly (Y, E, A, K)) is a random synthetic amino acid copolymer effective in the treatment of relapsing forms of multiple sclerosis (MS). Cop 1 binds promiscuously, with high affinity and in a peptide-specific manner to purified MS-associated HLA-DR2 (DRB1*1501) and rheumatoid arthritis-associated HLA-DR1 (DRB1*0101) or HLA-DR4 (DRB1*0401) molecules. In the present work at least 95% of added Cop 1 could be bound to recombinant “empty” HLA-DR1 and -DR4, and 80% could be bound to HLA-DR2 proteins. Amino acid composition, HPLC profiles, and sequencing patterns of Cop 1 eluted by acid extraction from HLA-DR molecules were similar to those of the unseparated Cop 1. Protruding N-terminal ends of Cop 1 bound to HLA-DR1, -DR2, or -DR4 molecules were then treated with aminopeptidase I, followed by elution, HPLC, and pool sequencing. In contrast to untreated or unbound Cop 1, this material exhibited distinct motifs at some positions with increases in levels of E at the first and second cycles, of K at the second and third cycles, and of Y (presumably at P1 of the bound peptide) at the third to fifth cycles, regardless of the HLA-DR molecule employed. No preference was seen at the following cycles that were mainly A. These first pooled HLA-DR binding epitopes provide clues to the components of Cop 1 that are biologically active in suppressing MS and possibly rheumatoid arthritis. The Journal of Immunology, 1999, 162:

[1]  Don C. Wiley,et al.  Crystal Structure of HLA-DR2 (DRA*0101, DRB1*1501) Complexed with a Peptide from Human Myelin Basic Protein , 1998, The Journal of experimental medicine.

[2]  L. Fugger,et al.  Synthetic amino acid copolymers that bind to HLA-DR proteins and inhibit type II collagen-reactive T cell clones. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J S Wolinsky,et al.  Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability , 1998, Neurology.

[4]  M. Fridkis-Hareli,et al.  Promiscuous binding of synthetic copolymer 1 to purified HLA-DR molecules , 1997, Journal of immunology.

[5]  D. Zaller,et al.  X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II. , 1997, Immunity.

[6]  D. Vignali,et al.  T cell receptor recognition of MHC class II-bound peptide flanking residues enhances immunogenicity and results in altered TCR V region usage. , 1997, Immunity.

[7]  F. Sinigaglia,et al.  HLA class II peptide binding specificity and autoimmunity. , 1997, Advances in immunology.

[8]  J. Strominger,et al.  Expression of Recombinant HLA-DR2 Molecules , 1996, The Journal of Biological Chemistry.

[9]  Søren Buus,et al.  T cell responses affected by aminopeptidase N (CD13)-mediated trimming of major histocompatibility complex class II-bound peptides. , 1996 .

[10]  J. Lamb,et al.  Induction of anergy in human T helper 0 cells by stimulation with altered T cell antigen receptor ligands. , 1996, Journal of immunology.

[11]  M. Sela,et al.  Copolymer 1 inhibits chronic relapsing experimental allergic encephalomyelitis induced by proteolipid protein (PLP) peptides in mice and interferes with PLP-specific T cell responses , 1996, Journal of Neuroimmunology.

[12]  J. W. Rose,et al.  Copolymer 1 reduces relapse rate and improves disability in relapsing‐remitting multiple sclerosis , 1995, Neurology.

[13]  M. Sela,et al.  Synthetic copolymer 1 and myelin basic protein do not require processing prior to binding to class II major histocompatibility complex molecules on living antigen-presenting cells. , 1995, Cellular immunology.

[14]  D. Wiley,et al.  Toxic shock syndrome toxin-1 complexed with a class II major histocompatibility molecule HLA-DR1. , 1994, Science.

[15]  H. Rammensee,et al.  Ligand motifs of HLA-DRB5*0101 and DRB1*1501 molecules delineated from self-peptides. , 1994, Journal of immunology.

[16]  M. Sela,et al.  Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells--specificity and promiscuity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Don C. Wiley,et al.  Three-dimensional structure of a human class II histocompatibility molecule complexed with superantigen , 1994, Nature.

[18]  Don C. Wiley,et al.  Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide , 1994, Nature.

[19]  J. Rothbard,et al.  Exploration of requirements for peptide binding to HLA DRB1*0101 and DRB1*0401. , 1994, Journal of immunology.

[20]  C Oseroff,et al.  Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones , 1994, The Journal of experimental medicine.

[21]  V. Gnau,et al.  Natural peptide ligand motifs of two HLA molecules associated with myasthenia gravis. , 1993, International immunology.

[22]  M F del Guercio,et al.  HLA DR4w4-binding motifs illustrate the biochemical basis of degeneracy and specificity in peptide-DR interactions. , 1993, Journal of immunology.

[23]  F. Sinigaglia,et al.  Promiscuous and allele-specific anchors in HLA-DR-binding peptides , 1993, Cell.

[24]  D. Wiley,et al.  Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1 , 1993, Nature.

[25]  William Arbuthnot Sir Lane,et al.  Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles , 1993, The Journal of experimental medicine.

[26]  R. Arnon,et al.  T suppressor hybridomas and interleukin‐2‐dependent lines induced by copolymer 1 or by spinal cord homogenate down‐regulate experimental allergic encephalomyelitis , 1993, European journal of immunology.

[27]  F. Sinigaglia,et al.  Identification of a motif for HLA-DR1 binding peptides using M13 display libraries , 1992, The Journal of experimental medicine.

[28]  Charles A. Janeway,et al.  Truncation variants of peptides isolated from MHC class II molecules suggest sequence motifs , 1992, Nature.

[29]  S. Buus,et al.  MHC molecules protect T cell epitopes against proteolytic destruction. , 1992, Journal of immunology.

[30]  William S. Lane,et al.  Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size , 1992, Nature.

[31]  S. Stevanović,et al.  Self-peptide released from class II HLA-DR1 exhibits a hydrophobic two- residue contact motif , 1992, The Journal of experimental medicine.

[32]  D. Wiley,et al.  The human class II MHC protein HLA-DR1 assembles as empty αβ heterodimers in the absence of antigenic peptide , 1992, Cell.

[33]  M. Sela,et al.  Synthetic copolymer 1 inhibits human T-cell lines specific for myelin basic protein. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[34]  A. Rudensky,et al.  Sequence analysis of peptides bound to MHC class II molecules , 1991, Nature.

[35]  J. Rothbard,et al.  Effect of natural polymorphism at residue 86 of the HLA-DR beta chain on peptide binding. , 1991, Journal of immunology.

[36]  S. Schreiber,et al.  Complete amino acid sequence of the FK506 and rapamycin binding protein, FKBP, isolated from calf thymus , 1991, Journal of protein chemistry.

[37]  M. Sela.  Suppressive activity of Cop 1 in EAE and its relevance to multiple sclerosis. , 1990 .

[38]  S. Blumberg,et al.  Streptomyces griseus aminopeptidase is a calcium-activated zinc metalloprotein. Purification and properties of the enzyme. , 1989, European journal of biochemistry.

[39]  M. Sela,et al.  Specific inhibition of the T-cell response to myelin basic protein by the synthetic copolymer Cop 1. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[40]  S. Wassertheil-Smoller,et al.  A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. , 1987, The New England journal of medicine.

[41]  R. Arnon,et al.  Effect of cyclophosphamide on suppressor cell activity in mice unresponsive to EAE. , 1979, Journal of immunology.

[42]  A. Meshorer,et al.  Suppression of experimental allergic encephalomyelitis in Rhesus monkeys by a synthetic basic copolymer. , 1974, Clinical immunology and immunopathology.

[43]  A. Meshorer,et al.  Suppression by several synthetic polypeptides of experimental allergic encephalomyelitis induced in guinea pigs and rabbits with bovine and human basic encephalitogen , 1973, European journal of immunology.

[44]  A. Meshorer,et al.  Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide , 1971, European journal of immunology.