Differential effects of treatment with a small-molecule VLA-4 antagonist before and after onset of relapsing EAE
- 15 December 2003
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 102 (13), 4464-4471
- https://doi.org/10.1182/blood-2003-03-0974
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. (Blood. 2003;102:4464-4471)Keywords
This publication has 26 references indexed in Scilit:
- Prolonged reversal of chronic experimental allergic encephalomyelitis using a small molecule inhibitor of α4 integrinJournal of Neuroimmunology, 2002
- Multiple Activation States of Integrin α4β1 Detected through Their Different Affinities for a Small Molecule LigandPublished by Elsevier BV ,1999
- Anti‐inflammatory activity of c(ILDV‐NH(CH2)5CO), a novel, selective, cyclic peptide inhibitor of VLA‐4‐mediated cell adhesionBritish Journal of Pharmacology, 1999
- A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease.The Journal of Experimental Medicine, 1996
- Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis.The Journal of Experimental Medicine, 1995
- Adhesion and costimulation of proliferative responses of human γδ T cells by interaction of VLA-4 and VLA-5 with fibronectinImmunology Letters, 1993
- Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma.The Journal of Experimental Medicine, 1993
- Induction of active and adoptive relapsing experimental autoimmune encephalomyelitis (EAE) using an encephalitogenic epitope of proteolipid proteinJournal of Neuroimmunology, 1992
- Prevention of experimental autoimmune encephalomyelitis by antibodies against α4βl integrinNature, 1992
- Analysis of T cell stimulation by superantigen plus major histocompatibility complex class II molecules or by CD3 monoclonal antibody: costimulation by purified adhesion ligands VCAM-1, ICAM-1, but not ELAM-1.The Journal of Experimental Medicine, 1991