title: Differential effects of treatment with a small-molecule VLA-4 antagonist before and after onset of relapsing EAE.
abstract: Interaction of very late antigen-4 (VLA-4) with its ligand vascular cell adhesion molecule-1 (VCAM-1) is required for central nervous system (CNS) migration of encephalitogenic T cells in relapsing experimental autoimmune encephalomyelitis (R-EAE). Anti-VLA-4 monoclonal antibody (mAb) treatment prior to EAE onset inhibits disease induction; however, treatment initiated after the appearance of clinical symptoms increases relapse rates, augments Th1 responses, and enhances epitope spreading perhaps due to the activation of costimulatory signals. To negate the potential costimulatory activity of intact anti-VLA-4, we examined the ability of BIO 5192, a small-molecule VLA-4 antagonist, to regulate active proteolipid protein 139-151 (PLP139-151)-induced R-EAE. BIO 5192 administered one week after peptide priming (ie, before clinical disease onset) delayed the clinical disease onset but led to severe disease exacerbation upon treatment removal. BIO 5192 treatment initiated during disease remission moderately enhanced clinical disease while mice were on treatment and also resulted in posttreatment exacerbation. Interestingly, BIO 5192 treatment begun at the peak of acute disease accelerated entrance into disease remission and inhibited relapses, but treatment removal again exacerbated disease. Enhanced disease was caused by the release of encephalitogenic cells from the periphery and the rapid accumulation of T cells in the CNS. Collectively, these results further demonstrate the complexity of VLA-4/VCAM interactions, particularly in a relapsing-remitting autoimmune disease.
authors.affiliation: Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Ave, Chicago, IL 60611, USA.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Theien
authors.forename: Carol L
authors.initials: CL
authors.lastname: Vanderlugt
authors.forename: Cheryl
authors.initials: C
authors.lastname: Nickerson-Nutter
authors.forename: Mark
authors.initials: M
authors.lastname: Cornebise
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Scott
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Perper
authors.forename: Eric T
authors.initials: ET
authors.lastname: Whalley
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects; D002490:Central Nervous System / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D004334:Drug Administration Schedule; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D020529:Multiple Sclerosis, Relapsing-Remitting; D018991:Myelin Proteolipid Protein / Q000276:immunology; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D010446:Peptide Fragments / Q000276:immunology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D012008:Recurrence; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
chemical_list: C475231:2-((1-(3,5-dichlorobenzenesulfonyl)pyrrolidine-2-carbonyl)amino)-4-(4-methyl-2-(methyl-(2-(4-(3-o-tolylureido)phenyl)acetyl)amino)pentanoylamino)butyric acid; D039041:Integrin alpha4beta1; D018991:Myelin Proteolipid Protein; D009842:Oligopeptides; D010446:Peptide Fragments; D010671:Phenylurea Compounds; D019010:Vascular Cell Adhesion Molecule-1; C435023:myelin proteolipid protein (139-151); C094242:myelin proteolipid protein (178-191)