Beneficial effect of modified peptide inhibitor of alpha4 integrins on experimental allergic encephalomyelitis in Lewis rats

J Neurosci Res. 2002 Jan 15;67(2):191-9. doi: 10.1002/jnr.10095.

Abstract

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.

MeSH terms

  • Animals
  • Antigens, CD / drug effects*
  • Antigens, CD / immunology
  • Astrocytes / drug effects
  • Astrocytes / immunology
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / immunology
  • Cell Adhesion / drug effects*
  • Cell Adhesion / immunology
  • Cell Adhesion Molecules / antagonists & inhibitors*
  • Cell Adhesion Molecules / immunology
  • Cell Communication / drug effects
  • Cell Communication / immunology
  • Cell Death / drug effects
  • Cell Death / immunology
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Central Nervous System / drug effects
  • Central Nervous System / immunology
  • Chemotaxis, Leukocyte / drug effects*
  • Chemotaxis, Leukocyte / immunology
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / immunology
  • Histocompatibility Antigens Class II / metabolism
  • Immunohistochemistry
  • Integrin alpha4
  • Lymphocytes / drug effects
  • Lymphocytes / immunology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Male
  • Peptides / pharmacology*
  • Peptides / therapeutic use
  • Rats
  • Rats, Inbred Lew
  • Receptors, Immunologic / drug effects
  • Receptors, Immunologic / immunology
  • Signaling Lymphocytic Activation Molecule Family
  • Stem Cells / drug effects
  • Stem Cells / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Antigens, CD
  • Cell Adhesion Molecules
  • Histocompatibility Antigens Class II
  • Peptides
  • Receptors, Immunologic
  • SLAMF7 protein, human
  • Signaling Lymphocytic Activation Molecule Family
  • Vascular Cell Adhesion Molecule-1
  • Integrin alpha4