Amelioration of Proteolipid Protein 139–151-Induced Encephalomyelitis in SJL Mice by Modified Amino Acid Copolymers and Their Mechanisms

Authors

Joel N.H. Stern, Harvard University
Zsolt Illés, Harvard Institute of Medicine
Jay Reddy, University of Nebraska - LincolnFollow
Derin B. Keskin, Harvard University
Eric Sheu, Harvard University
Masha Fridkis-Hareli, Harvard University
Hiroyuki Nishimura, Harvard University
Celia F. Brosnan, Albert Einstein College of Medicine
Laura Santambrogio, Harvard Institute of Medicine
Vijay K. Kuchroo, Harvard Institute of Medicine
Jack L. Strominger, Harvard University

Document Type

Article

Date of this Version

2004

Citation

Proceedings of the National Academy of Sciences (August 10, 2004) 101(32): 11,743-11,748. DOI: 10.1073/pnas.0403832101.

Comments

Copyright 2004, PNAS. Used by permission.

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-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 copolymerspecific 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.