Discordant effects of anti-VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis.
Initial migration of encephalitogenic T cells to the central nervous system (CNS) in relapsing experimental autoimmune encephalomyelitis (R-EAE), an animal model of multiple sclerosis (MS), depends on the interaction of the alpha4 integrin (VLA-4) expressed on activated T cells with VCAM-1 expressed on activated cerebrovascular endothelial cells. Alternate homing mechanisms may be employed by infiltrating inflammatory cells after disease onset. We thus compared the ability of anti-VLA-4 to regulate proteolipid protein (PLP) 139-151-induced R-EAE when administered either before or after disease onset. Preclinical administration of anti-VLA-4 either to naive recipients of primed encephalitogenic T cells or to mice 1 week after peptide priming, i.e., before clinical disease onset, inhibited the onset and severity of clinical disease. In contrast, Ab treatment either at the peak of acute disease or during remission exacerbated disease relapses and increased the accumulation of CD4(+) T cells in the CNS. Most significantly, anti-VLA-4 treatment either before or during ongoing R-EAE enhanced Th1 responses to both the priming peptide and endogenous myelin epitopes released secondary to acute tissue damage. Collectively, these results suggest that treatment with anti-VLA-4 Ab has multiple effects on the immune system and may be problematic in treating established autoimmune diseases such as MS.
Theien
B E
BE
Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611, USA.
Vanderlugt
C L
CL
Eagar
T N
TN
Nickerson-Nutter
C
C
Nazareno
R
R
Kuchroo
V K
VK
Miller
S D
SD
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation; D002455:Cell Division; D002490:Central Nervous System / Q000276:immunology; D016207:Cytokines / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy; D005260:Female; D007167:Immunotherapy / Q000379:methods; D039041:Integrin alpha4beta1; D016023:Integrins / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D012333:RNA, Messenger; D016201:Receptors, Lymphocyte Homing / Q000276:immunology*; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D000911:Antibodies, Monoclonal; D016207:Cytokines; D039041:Integrin alpha4beta1; D016023:Integrins; D012333:RNA, Messenger; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; D007371:Interferon-gamma