Amelioration of proteolipid protein 139-151-induced encephalomyelitis in SJL mice by modified amino acid copolymers and their mechanisms

Joel N H Stern, Zsolt Illés, Jayagopama Reddy, Derin B. Keskin, Eric Sheu, Masha Fridkis-Hareli, Hiroyuki Nishimura, Celia F. Brosnan, Laura Santambrogio, Vijay K. Kuchroo, Jack L. Strominger

Research output: Contribution to journalArticle

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Abstract

Copolymer 1 [Cop1, glatiramer acetate, Copaxone, poly(Y,E,A,K)n] is widely used in the treatment of relapsing/remitting multiple sclerosis in which it reduces the frequency of relapses by ≈30%. In the present study, copolymers with modified amino acid compositions (based on the binding motif of myelin basic protein 85-99 to HLA-DR2) have been developed with the aim of suppressing multiple sclerosis more effectively. The enhanced efficacy of these copolymers in experimental autoimmune encephalomyelitis (EAE) induced in SJL/J mice with proteolipid protein 139-151 was demonstrated by using three protocols: (i) simultaneous administration of autoantigen and copolymer (termed prevention), (ii) pretreatment with copolymers (vaccination), or (iii) administration of copolymers after disease onset (treatment). Strikingly, in the treatment protocol administration of soluble VWAK and FYAK after onset of disease led to stasis of its progression and suppression of histopathological evidence of EAE. The mechanisms by which these effects are achieved have been examined in several types of assays: binding of copolymers to I-As in competition with proteolipid protein 139-151 (blocking), cytokine production by T cells (T helper 2 polarization), and transfer of protection by CD3+ splenocytes or, notably, by copolymer-specific T cell lines (induction of regulatory T cells). The generation of these copolymer-specific regulatory T cells that secrete IL-4 and IL-10 and are independent of the immunizing autoantigen is very prominent among the multiple mechanisms that account for the observed suppressive effect of copolymers in EAE.

Original languageEnglish (US)
Pages (from-to)11743-11748
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

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Encephalomyelitis
Autoimmune Experimental Encephalomyelitis
Autoantigens
Regulatory T-Lymphocytes
Amino Acids
HLA-DR2 Antigen
T-Lymphocytes
Relapsing-Remitting Multiple Sclerosis
Th2 Cells
Clinical Protocols
Interleukin-4
Interleukin-10
Multiple Sclerosis
Vaccination
Cytokines
Recurrence
Cell Line
Therapeutics
myelin proteolipid protein (139-151)
Glatiramer Acetate

Keywords

  • Autoimmunity
  • Cytokines
  • Multiple sclerosis
  • Peptides
  • T cells

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Amelioration of proteolipid protein 139-151-induced encephalomyelitis in SJL mice by modified amino acid copolymers and their mechanisms. / Stern, Joel N H; Illés, Zsolt; Reddy, Jayagopama; Keskin, Derin B.; Sheu, Eric; Fridkis-Hareli, Masha; Nishimura, Hiroyuki; Brosnan, Celia F.; Santambrogio, Laura; Kuchroo, Vijay K.; Strominger, Jack L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 32, 10.08.2004, p. 11743-11748.

Research output: Contribution to journalArticle

Stern, Joel N H ; Illés, Zsolt ; Reddy, Jayagopama ; Keskin, Derin B. ; Sheu, Eric ; Fridkis-Hareli, Masha ; Nishimura, Hiroyuki ; Brosnan, Celia F. ; Santambrogio, Laura ; Kuchroo, Vijay K. ; Strominger, Jack L. / Amelioration of proteolipid protein 139-151-induced encephalomyelitis in SJL mice by modified amino acid copolymers and their mechanisms. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 32. pp. 11743-11748.
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abstract = "Copolymer 1 [Cop1, glatiramer acetate, Copaxone, poly(Y,E,A,K)n] is widely used in the treatment of relapsing/remitting multiple sclerosis in which it reduces the frequency of relapses by ≈30{\%}. In the present study, copolymers with modified amino acid compositions (based on the binding motif of myelin basic protein 85-99 to HLA-DR2) have been developed with the aim of suppressing multiple sclerosis more effectively. The enhanced efficacy of these copolymers in experimental autoimmune encephalomyelitis (EAE) induced in SJL/J mice with proteolipid protein 139-151 was demonstrated by using three protocols: (i) simultaneous administration of autoantigen and copolymer (termed prevention), (ii) pretreatment with copolymers (vaccination), or (iii) administration of copolymers after disease onset (treatment). Strikingly, in the treatment protocol administration of soluble VWAK and FYAK after onset of disease led to stasis of its progression and suppression of histopathological evidence of EAE. The mechanisms by which these effects are achieved have been examined in several types of assays: binding of copolymers to I-As in competition with proteolipid protein 139-151 (blocking), cytokine production by T cells (T helper 2 polarization), and transfer of protection by CD3+ splenocytes or, notably, by copolymer-specific T cell lines (induction of regulatory T cells). The generation of these copolymer-specific regulatory T cells that secrete IL-4 and IL-10 and are independent of the immunizing autoantigen is very prominent among the multiple mechanisms that account for the observed suppressive effect of copolymers in EAE.",
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AU - Illés, Zsolt

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AU - Keskin, Derin B.

AU - Sheu, Eric

AU - Fridkis-Hareli, Masha

AU - Nishimura, Hiroyuki

AU - Brosnan, Celia F.

AU - Santambrogio, Laura

AU - Kuchroo, Vijay K.

AU - Strominger, Jack L.

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