Beneficial effect of modified peptide inhibitor of alpha4 integrins on experimental allergic encephalomyelitis in Lewis rats.
An important event in the pathogenesis of the autoimmune disease multiple sclerosis (MS) is the recruitment of lymphocytes and inflammatory macrophages to the central nervous system (CNS). Recruitment requires adhesive interactions between the leukocytes and the microvascular endothelium, perivascular cells, and astrocytes in the CNS parenchyma. Previous studies using an animal model of MS, experimental allergic encephalomyelitis (EAE), have shown the involvement of the alpha4 integrin VLA-4 (beta4beta1). In the present study, the effect of a modified peptide inhibitor of alpha4 integrins on the clinical course and leukocyte infiltration during EAE is investigated. EAE was either induced actively, by immunizing Lewis rats with whole guinea pig MBP, or passively, by transfer of an MBP-specific T cell line. Treatment with the inhibitor (CS1 ligand mimic) completely prevented both clinical signs and cellular infiltration in passively induced EAE. Peptide treatment of actively induced EAE, which has a more severe disease course than the transfer model, significantly reduced clinical signs although the recruitment of inflammatory cells and induction of MHC class II expression was not prevented. The alpha4 inhibitor did inhibit the adhesion of lymphocytes to primary astrocytes in vitro suggesting a role for astrocyte-leukocyte interactions in the pathogenesis of induced EAE. Astrocytes were found to express an extracellular matrix protein distinct from fibronectin, which shows immune cross-reactivity with the CS1 domain of fibronectin. Our results show that small-molecule inhibitors of alpha4 integrins act therapeutically in EAE possibly by interfering with cell adhesion events involved in this autoimmune disease.
van der Laan
Luc J W
LJ
Department of Cell Biology and Immunology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands.
van der Goes
Annette
A
Wauben
Marca H M
MH
Ruuls
Sigrid R
SR
Döpp
Ed A
EA
De Groot
Corline J A
CJ
Kuijpers
Taco W
TW
Elices
Mariano J
MJ
Dijkstra
Christine D
CD
D000818:Animals; D015703:Antigens, CD / Q000187:drug effects* / Q000276:immunology; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects* / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007150:Immunohistochemistry; D039441:Integrin alpha4; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D011971:Receptors, Immunologic / Q000187:drug effects / Q000276:immunology; D000071176:Signaling Lymphocytic Activation Molecule Family; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D011971:Receptors, Immunologic; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4