Modified amino acid copolymers suppress myelin basic protein 85-99-induced encephalomyelitis in humanized mice through different effects on T cells.

Abstract

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.

• Authors: Zsolt Illés, Joel N H Stern, Jayagopala Reddy, Hanspeter Waldner, Marcin P Mycko, Celia F Brosnan, Stephan Ellmerich, Daniel M Altmann, Laura Santambrogio, Jack L Strominger, Vijay K Kuchroo
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 32 Pg. 11749-54 (Aug 10 2004) ISSN: 0027-8424 [Print] United States
• PMID: 15292513 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytokines
• HLA-DR2 Antigen
• Myelin Basic Protein
• Peptide Fragments
• Peptides
• Receptors, Antigen, T-Cell
• myelin basic protein 85-99
• Glatiramer Acetate

Topics

• Amino Acid Sequence
• Animals
• Cytokines (drug effects, metabolism)
• Drug Therapy, Combination
• Encephalomyelitis, Autoimmune, Experimental (chemically induced, drug therapy, prevention & control)
• Glatiramer Acetate
• HLA-DR2 Antigen
• Humans
• Mice
• Mice, Transgenic
• Myelin Basic Protein (pharmacology)
• Peptide Fragments (administration & dosage, pharmacology, therapeutic use)
• Peptides (administration & dosage, therapeutic use)
• Receptors, Antigen, T-Cell (immunology)
• T-Lymphocytes (drug effects, immunology)
• Treatment Outcome
• Vaccination