Abstract
The MOG35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice is a useful animal model to explore therapeutic approaches to T cell-mediated autoimmune diseases because the dominant T-cell epitope(s) have been defined. It is rational that antigen-specific immunosuppression can be induced by using MHC-peptide complexes as specific TCR ligand(s) that interact with autoreactive T cells in the absence of co-stimulation. In this study, a soluble divalent MOG35-55/I-A(b) fusion protein (MOG35-55/I-A(b) dimer) was constructed to specifically target the autoreactive CD4+ T cells in the EAE mouse. Intraperitoneal administration of the MOG35-55/I-A(b) dimer significantly delayed and ameliorated EAE symptoms by reducing EAE-related inflammation in the mouse CNS and reducing encephalitogenic Th1 and Th17 cells in the peripheral lymphoid organs. We observed that dimer intervention at a concentration of 1.2 nM suppressed MOG35-55 peptide-specific 2D2 transgenic T cells (2D2 T cells) proliferation by over 90% after in vitro activation with MOG35-55 peptide. The mechanisms involved in this antigen-specific dimer-mediated suppression were found to be downregulated TCR-CD3 expression as well as upregulated expression of membrane-bound TGF-β (mTGF-β) and IL-10 suppressive cytokines by the autoreactive CD4+ T cells. Collectively, our data demonstrates that soluble divalent MHC class II molecules can abrogate pathogenic T cells in EAE. Furthermore, our data suggests that this strategy may provide an efficient and clinically useful option to treat autoimmune diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / pathology
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Encephalomyelitis, Autoimmune, Experimental / drug therapy*
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Encephalomyelitis, Autoimmune, Experimental / physiopathology
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Epitopes, T-Lymphocyte / immunology*
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Histocompatibility Antigens Class II / immunology
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Histocompatibility Antigens Class II / metabolism
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Mice
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Mice, Inbred C57BL
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Myelin-Oligodendrocyte Glycoprotein / administration & dosage*
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Myelin-Oligodendrocyte Glycoprotein / metabolism
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Peptide Fragments / administration & dosage
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Peptide Fragments / metabolism
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Receptors, Antigen, T-Cell / immunology
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Recombinant Fusion Proteins / administration & dosage*
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T-Lymphocytes / immunology
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T-Lymphocytes / pathology*
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / metabolism
Substances
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Epitopes, T-Lymphocyte
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Histocompatibility Antigens Class II
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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Receptors, Antigen, T-Cell
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Recombinant Fusion Proteins
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Transforming Growth Factor beta
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myelin oligodendrocyte glycoprotein (35-55)
Grants and funding
This publication was made possible by grants from the National Natural Science Foundation of China (No.30801017, No.30972697), the “973” and the “863” project of the Chinese Department of Science and Technology (2007CB512900, 2008AA02Z113), and the International Science and Technology Cooperation Program of China (2011DFA31030) and Deutsche Forschungsgemeinschaft (SFB/Transregio TRR60). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.