Modified Amino Acid Copolymers Suppress Myelin Basic Protein 85-99-Induced Encephalomyelitis in Humanized Mice through Different Effects on T Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-08, Vol.101 (32), p.11749-11754
• Main Authors: Illés, Zsolt, Joel N. H. Stern, Reddy, Jayagopala, Waldner, Hanspeter, Mycko, Marcin P., Brosnan, Celia F., Ellmerich, Stephan, Altmann, Daniel M., Santambrogio, Laura, Strominger, Jack L., Kuchroo, Vijay K.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino acids; Animals; Biological Sciences; Central nervous system; Copolymers; Cytokines; Cytokines - drug effects; Cytokines - secretion; Demyelinating diseases; Drug Therapy, Combination; Encephalomyelitis, Autoimmune, Experimental - chemically induced; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Glatiramer Acetate; HLA-DR2 Antigen; Humans; Immunization; Immunology; Mice; Mice, Transgenic; Myelin Basic Protein - pharmacology; Nervous system diseases; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Peptides - administration & dosage; Peptides - therapeutic use; Proteins; Receptors, Antigen, T-Cell - immunology; Splenocytes; T cell antigen receptors; T lymphocytes; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Treatment Outcome; Vaccination
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0403833101

A humanized mouse bearing the HLA-DR2 (DRA/DRB1*1501) protein associated with multiple sclerosis (MS) and the myelin basic protein (MBP) 85-99-specific HLA-DR2-restricted T cell receptor from an MS patient has been used to examine the effectiveness of modified amino acid copolymers poly(F,Y,A,K)n and poly-(V,W,A,K)n in therapy of MBP 85-99-induced experimental autoimmune encephalomyelitis (EAE) in comparison to Copolymer 1 [Copaxone, poly(Y,E,A,K)n]. The copolymers were designed to optimize binding to HLA-DR2. Vaccination, prevention, and treatment of MBP-induced EAE in the humanized mice with copolymers FYAK and VWAK ameliorated EAE more effectively than Copolymer 1, reduced the number of pathological lesions, and prevented the up-regulation of human HLA-DR on CNS microglia. Moreover, VWAK inhibited MBP 85-99-specific T cell proliferation more efficiently than either FYAK or Copolymer 1 and induced anergy of HLA-DR2-restricted transgenic T cells as its principle mechanism. In contrast, FYAK induced proliferation and a pronounced production of the antiinflammatory T helper 2 cytokines IL-4 and IL-10 from nontransgenic T cells as its principle mechanism of immunosuppression. Thus, copolymers generated by using different amino acids inhibited disease using different mechanisms to regulate T cell responses.