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

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 approximately 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-A(s) 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.

• Authors: Joel N H Stern, Zsolt Illés, Jayagopala Reddy, Derin B Keskin, Eric Sheu, Masha Fridkis-Hareli, Hiroyuki Nishimura, Celia F Brosnan, Laura Santambrogio, Vijay K Kuchroo, Jack L Strominger
• 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. 11743-8 (Aug 10 2004) ISSN: 0027-8424 [Print] United States
• PMID: 15292514 (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
• Myelin Proteolipid Protein
• Peptide Fragments
• Peptides
• myelin basic protein 85-99
• myelin proteolipid protein (139-151)
• Glatiramer Acetate

Topics

• Adoptive Transfer
• Amino Acid Sequence
• Animals
• Cytokines (drug effects, metabolism)
• Encephalomyelitis, Autoimmune, Experimental (chemically induced, drug therapy, prevention & control)
• Glatiramer Acetate
• HLA-DR2 Antigen
• Mice
• Mice, Inbred Strains
• Multiple Sclerosis (drug therapy)
• Myelin Basic Protein (administration & dosage, therapeutic use)
• Myelin Proteolipid Protein (administration & dosage, pharmacology)
• Peptide Fragments (administration & dosage, pharmacology, therapeutic use)
• Peptides (administration & dosage, therapeutic use)
• Protein Binding
• T-Lymphocytes (drug effects, immunology, transplantation)
• Vaccination