Journal Article

Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines

Ruth Maron, Anthony J. Slavin, Ethan Hoffmann, Yoshinori Komagata and Howard L. Weiner

in International Immunology

Published on behalf of Japanese Society for Immunology

Volume 14, issue 2, pages 131-138
Published in print February 2002 | ISSN: 0953-8178
Published online February 2002 | e-ISSN: 1460-2377 | DOI: http://dx.doi.org/10.1093/intimm/14.2.131
Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines

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Oral tolerance to myelin basic protein (MBP) is an effective antigen-specific method to suppress experimental allergic encephalomyelitis (EAE). Glatiramer acetate [copolymer 1 (Cop1)] is a synthetic copolymer designed to mimic MBP which suppresses EAE, is used parenterally to treat multiple sclerosis (MS) and is being tested orally for efficacy in MS. We investigated the immunologic properties of Cop1 to determine the degree to which its effects were antigen specific using MBP TCR transgenic mice. Immunization of MBP TCR transgenic mice fed Cop1, MBP or MBP Ac1–11 resulted in decreased proliferation, and IL-2, IL-6 and IFN-γ production, and increased secretion of IL-10 and transforming growth factor (TGF)-β in Cop1-fed animals. IFN-γ was decreased, and IL-10 and TGF-β were increased in non-immunized mice fed Cop1 and stimulated in vitro with MBP. No such effects were observed in ovalbumin TCR transgenic mice. To determine if the effects of Cop1 were specific to MBP TCR-bearing cells, MBP TCR transgenic Rag2–/– mice were immunized and re-stimulated in vitro with Cop1. We found a marked increase in IL-4 and similar increases in IL-4 after feeding Cop1. In disease models, feeding Cop1 suppressed EAE in MBP TCR transgenic mice, (PL/J × SJL)F1 mice, and in myelin oligodendrocyte glycoprotein-induced EAE in NOD mice. Oral Cop1 had no effect on collagen-induced arthritis. These results demonstrate that Cop1 is active orally in an antigen-specific fashion, and may function as an altered peptide ligand for MBP-specific TCR-bearing cells by decreasing pro-inflammatory cytokines (IFN-γ) and increasing anti-inflammatory cytokines (IL-4, IL-10 and TGF-β).

Keywords: anti-inflammatory cytokines; copolymer 1; experimental allergic encephalomyelitis; myelin basic protein; oral tolerance; transforming growth factor-β; CFA complete Freund's adjuvant; CIA collagen-induced arthritis; Cop1 copolymer 1; MBP myelin basic protein; MOG myelin oligodendrocyte glycoprotein; MS multiple sclerosis; MT Mycobacterium tuberculosis H37RA; OVA ovalbumin; TGF transforming growth factor

Journal Article.  5351 words.  Illustrated.

Subjects: Immunology ; Biological Sciences

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