Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system.
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-alpha and TCR-beta 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.
Yan
Shirley ShiDu
SS
Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York, USA. sdy1@columbia.edu
Wu
Zhi-Ying
ZY
Zhang
Hui Ping
HP
Furtado
Glaucia
G
Chen
Xi
X
Yan
Shi Fang
SF
Schmidt
Ann Marie
AM
Brown
Chris
C
Stern
Alan
A
LaFaille
Juan
J
Chess
Leonard
L
Stern
David M
DM
Jiang
Hong
H
D000818:Animals; D002460:Cell Line; D002490:Central Nervous System / Q000276:immunology / Q000502:physiology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009418:S100 Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*
D039841:Leukocyte L1 Antigen Complex; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; C074815:myelin basic protein 1-9