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

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

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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 auto-immune 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.

Original languageEnglish (US)
Pages (from-to)11749-11754
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number32
DOIs
StatePublished - Aug 10 2004

Keywords

  • Autoimmunity
  • CNS
  • DRB1*1501
  • Microglia
  • Multiple sclerosis

ASJC Scopus subject areas

  • General

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