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.

[1]  H. Weiner,et al.  T-cell recognition of myelin basic protein. , 1991, Immunology today.

[2]  V. Kuchroo,et al.  An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. , 1995, Immunity.

[3]  K. Garcia,et al.  Immunomodulation of Experimental Autoimmune Encephalomyelitis with Ordered Peptides Based on MHC-TCR Binding Motifs1 , 2001, The Journal of Immunology.

[4]  Manjit,et al.  Neurology , 1912, NeuroImage.

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

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

[7]  C. Brosnan,et al.  Novel synthetic amino acid copolymers that inhibit autoantigen-specific T cell responses and suppress experimental autoimmune encephalomyelitis. , 2002, The Journal of clinical investigation.

[8]  R. Spielman,et al.  The genetics of susceptibility to multiple sclerosis. , 1982, Epidemiologic reviews.

[9]  T. Tabira,et al.  Identification of autoimmune T-cells among in vivo expanded CD25+ T-cells in multiple sclerosis , 1998, Journal of Neuroimmunology.

[10]  A. Gaur,et al.  Amelioration of autoimmune encephalomyelitis by myelin basic protein synthetic peptide-induced anergy. , 1992, Science.

[11]  U. Utz,et al.  Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein , 1996, Nature.

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

[13]  V. Kuchroo,et al.  IL-10, a key effector regulatory cytokine in experimental autoimmune encephalomyelitis. , 2003, Journal of autoimmunity.

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

[15]  L. Nagelkerken,et al.  Role of Th1 and Th2 cells in autoimmune demyelinating disease. , 1998, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[16]  H. Weiner,et al.  IL-10 is critical in the regulation of automimmune encephalomyelitis as demonstrated by studies of IL-10 and IL-4 deficient and transgenic mice , 1998, Journal of Neuroimmunology.

[17]  J. Frank,et al.  Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand , 2000, Nature Medicine.

[18]  A. Evans,et al.  Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial , 2000, Nature Medicine.

[19]  A. Ben-nun,et al.  Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: Reactivity to the extracellular domain of MOG is directed against three main regions , 1997, European journal of immunology.

[20]  Jan Engberg,et al.  Visualization of Myelin Basic Protein (Mbp) T Cell Epitopes in Multiple Sclerosis Lesions Using a Monoclonal Antibody Specific for the Human Histocompatibility Leukocyte Antigen (Hla)-Dr2–Mbp 85–99 Complex , 2000, The Journal of experimental medicine.

[21]  William Arbuthnot Sir Lane,et al.  Binding motifs of copolymer 1 to multiple sclerosis- and rheumatoid arthritis-associated HLA-DR molecules. , 1999, Journal of immunology.

[22]  L. Fugger,et al.  Synthetic peptides that inhibit binding of the myelin basic protein 85-99 epitope to multiple sclerosis-associated HLA-DR2 molecules and MBP-specific T-cell responses. , 2001, Human immunology.

[23]  V. Kuchroo,et al.  Myelin proteolipid protein-specific CD4+CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[24]  V. Kuchroo,et al.  Detection of Autoreactive Myelin Proteolipid Protein 139–151-Specific T Cells by Using MHC II (IAs) Tetramers1 , 2003, The Journal of Immunology.

[25]  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.

[26]  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.

[27]  S. Nelson,et al.  A phase I trial of solubilized DR2:MBP84-102 (AG284) in multiple sclerosis , 2000, Neurology.

[28]  R J Albertini,et al.  T cells responsive to myelin basic protein in patients with multiple sclerosis. , 1990, Science.

[29]  V. Kuchroo,et al.  Induction of experimental allergic encephalomyelitis by myelin proteolipid-protein-specific T cell clones and synthetic peptides. , 1991, Pathobiology : journal of immunopathology, molecular and cellular biology.

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

[31]  D. Keskin,et al.  Amelioration of proteolipid protein 139-151-induced encephalomyelitis in SJL mice by modified amino acid copolymers and their mechanisms. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[32]  C. Brosnan,et al.  Modified amino acid copolymers suppress myelin basic protein 85-99-induced encephalomyelitis in humanized mice through different effects on T cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[33]  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.

[34]  D. Mitchell,et al.  Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon gamma and tumor necrosis factor alpha production , 1994, The Journal of experimental medicine.

[35]  R. Sobel,et al.  Identification of an encephalitogenic determinant of myelin proteolipid protein for SJL mice. , 1989, Journal of immunology.

[36]  A. Sette,et al.  T cell recognition of immunodominant and cryptic proteolipid protein epitopes in humans , 1994, Journal of Neuroimmunology.

[37]  L. Fugger,et al.  A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor , 1999, Nature Genetics.

[38]  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.

[39]  J. Hillert,et al.  The HLA-Dw2 haplotype segregates closely with multiple sclerosis in multiplex families , 1994, Journal of Neuroimmunology.

[40]  Genetic factors in multiple sclerosis. , 1993, JAMA.

[41]  J. Leonard,et al.  Regulation of Experimental Autoimmune Encephalomyelitis by Interleukin‐12 , 1996, Annals of the New York Academy of Sciences.

[42]  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.