Discordant effects of anti-VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis

B. E. Theien, C. L. Vanderlugt, T. N. Eagar, C. Nickerson-Nutter, R. Nazareno, V. K. Kuchroo, S. D. Miller

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

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 α4 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.

Original languageEnglish (US)
Pages (from-to)995-1006
Number of pages12
JournalJournal of Clinical Investigation
Volume107
Issue number8
StatePublished - 2001

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Integrin alpha4beta1
Autoimmune Experimental Encephalomyelitis
T-Lymphocytes
Multiple Sclerosis
Central Nervous System
Peptides
Vascular Cell Adhesion Molecule-1
Acute Disease
Myelin Sheath
Integrins
Autoimmune Diseases
Epitopes
Immune System
Endothelial Cells
Animal Models
Recurrence

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Theien, B. E., Vanderlugt, C. L., Eagar, T. N., Nickerson-Nutter, C., Nazareno, R., Kuchroo, V. K., & Miller, S. D. (2001). Discordant effects of anti-VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis. Journal of Clinical Investigation, 107(8), 995-1006.

Discordant effects of anti-VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis. / Theien, B. E.; Vanderlugt, C. L.; Eagar, T. N.; Nickerson-Nutter, C.; Nazareno, R.; Kuchroo, V. K.; Miller, S. D.

In: Journal of Clinical Investigation, Vol. 107, No. 8, 2001, p. 995-1006.

Research output: Contribution to journalArticle

Theien, BE, Vanderlugt, CL, Eagar, TN, Nickerson-Nutter, C, Nazareno, R, Kuchroo, VK & Miller, SD 2001, 'Discordant effects of anti-VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis', Journal of Clinical Investigation, vol. 107, no. 8, pp. 995-1006.
Theien BE, Vanderlugt CL, Eagar TN, Nickerson-Nutter C, Nazareno R, Kuchroo VK et al. Discordant effects of anti-VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis. Journal of Clinical Investigation. 2001;107(8):995-1006.
Theien, B. E. ; Vanderlugt, C. L. ; Eagar, T. N. ; Nickerson-Nutter, C. ; Nazareno, R. ; Kuchroo, V. K. ; Miller, S. D. / Discordant effects of anti-VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis. In: Journal of Clinical Investigation. 2001 ; Vol. 107, No. 8. pp. 995-1006.
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