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 journalArticle

37 Citations (Scopus)

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
Externally publishedYes

Fingerprint

HLA-DR2 Antigen
Encephalomyelitis
T-Lymphocytes
Amino Acids
Multiple Sclerosis
HLA-DR alpha-Chains
Myelin Basic Protein
Microglia
HLA-DR Antigens
T-Cell Antigen Receptor
Interleukin-4
Interleukin-10
Immunosuppression
Vaccination
Anti-Inflammatory Agents
Up-Regulation
Cell Proliferation
Cytokines
myelin basic protein 85-99
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Modified amino acid copolymers suppress myelin basic protein 85-99-induced encephalomyelitis in humanized mice through different effects on T cells. / Illés, Zsolt; Stern, Joel N H; Reddy, Jayagopala; Waldner, Hanspeter; Mycko, Marcin P.; Brosnan, Celia F.; Ellmerich, Stephan; Altmann, Daniel M.; Santambrogio, Laura; Strominger, Jack L.; Kuchroo, Vijay K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 32, 10.08.2004, p. 11749-11754.

Research output: Contribution to journalArticle

Illés, Zsolt ; Stern, Joel N H ; Reddy, Jayagopala ; Waldner, Hanspeter ; Mycko, Marcin P. ; Brosnan, Celia F. ; Ellmerich, Stephan ; Altmann, Daniel M. ; Santambrogio, Laura ; Strominger, Jack L. ; Kuchroo, Vijay K. / Modified amino acid copolymers suppress myelin basic protein 85-99-induced encephalomyelitis in humanized mice through different effects on T cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 32. pp. 11749-11754.
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AU - Reddy, Jayagopala

AU - Waldner, Hanspeter

AU - Mycko, Marcin P.

AU - Brosnan, Celia F.

AU - Ellmerich, Stephan

AU - Altmann, Daniel M.

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AU - Strominger, Jack L.

AU - Kuchroo, Vijay K.

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