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Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system

Nature Medicine volume 9, pages 287–293 (2003)Cite this article

Abstract

Multiple sclerosis (MS) is a devastating neuroinflammatory disorder of the central nervous system (CNS) in which T cells that are reactive with major components of myelin sheaths have a central role. The receptor for advanced glycation end products (RAGE) is present on T cells, mononuclear phagocytes and endothelium. Its pro-inflammatory ligands, S100-calgranulins, are upregulated in MS and in the related rodent model, experimental autoimmune encephalomyelitis (EAE). Blockade of RAGE suppressed EAE when disease was induced by myelin basic protein (MBP) peptide or encephalitogenic T cells, or when EAE occurred spontaneously in T-cell receptor (TCR)-transgenic mice devoid of endogenous TCR-α and TCR-β chains. Inhibition of RAGE markedly decreased infiltration of the CNS by immune and inflammatory cells. Transgenic mice with targeted overexpression of dominant-negative RAGE in CD4+ T cells were resistant to MBP-induced EAE. These data reinforce the importance of RAGE-ligand interactions in modulating properties of CD4+ T cells that infiltrate the CNS.

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Figure 1: Immunolocalization of RAGE and S100 antigens in spinal cord tissue from MS patients.
Figure 2: Effect of RAGE blockade on EAE induced by 1–9NAc MBP.
Figure 3: Mechanisms of sRAGE-mediated suppression of EAE induced by 1–9NAc MBP.
Figure 4: Studies with 1AE10 cells.
Figure 5: Effect of sRAGE on spontaneous EAE in Tα−β− mice.
Figure 6: Effect of RAGE on 1–9NAc MBP-induced EAE in transgenic mice with targeted overexpression of RAGE in CD4+ T cells and mononuclear phagocytes.

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Acknowledgements

This work was supported by grants from the US Public Health Service (NS42855, AI44927, AI46132) and the Multiple Sclerosis Society (RG2938). We thank A.P. Hays for providing human MS samples and suggestions.

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Authors and Affiliations

  1. Departments of Pathology, Surgery, Medicine, and Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, New York, USA

    Shirley ShiDu Yan, Zhi-Ying Wu, Hui Ping Zhang, Shi Fang Yan, Ann Marie Schmidt, Chris Brown, Alan Stern, Leonard Chess, David M. Stern & Hong Jiang

  2. Department of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, People's Republic of China

    Zhi-Ying Wu

  3. Skirball Institute of Biomedical Science, New York University, New York, New York, USA

    Glaucia Furtado & Juan Lafaille

  4. Department of Neurology, New York University Medical Center, New York, New York, USA

    Xi Chen

  5. School of Medicine, Medical College of Georgia, Augusta, Georgia, USA

    David M. Stern

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Correspondence to Shirley ShiDu Yan.

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Yan, S., Wu, ZY., Zhang, H. et al. Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system. Nat Med 9, 287–293 (2003). https://doi.org/10.1038/nm831

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