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

doi:10.1073/pnas.0403833101

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

^†Center for Neurologic Diseases, Harvard Institute of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; ^§Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138; ^∥Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461; ^††Department of Infectious Diseases, Imperial College, London WC1E 6BT, United Kingdom; and ^‡‡Department of Cancer Immunology and AIDS, Dana–Farber Cancer Institute, Boston, MA 02115

Contributed by Jack L. Strominger, June 22, 2004

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 autoimmune 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.

Footnotes

↵ §§ To whom correspondence may be addressed. E-mail: jlstrom{at}fas.harvard.edu or vkuchroo{at}rics.bwh.harvard.edu.
↵ ‡ Z.I. and J.N.H.S. contributed equally to this work.
↵ ¶ Present address: Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Kopcinskiego Strasse 22, 90-153 Lodz, Poland.
↵ ¶¶ The development of the copolymers for clinical trial of MS has been licensed by Harvard University to Peptimmune (Boston). J.L.S. is Chairman of the Scientific Advisory Board and has an equity interest in Peptimmune.
Abbreviations: MS, multiple sclerosis; MHC II, MHC class II; MBP, myelin basic protein; EAE, experimental autoimmune encephalomyelitis; TCR, T cell receptor; tg, transgenic; Cop1, Copolymer 1; Th2, T helper 2; CFA, complete Freund's adjuvant; APC, antigen-presenting cell.