Discordant effects of anti–VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis
Bradley E. Theien, … , Vijay K. Kuchroo, Stephen D. Miller
Bradley E. Theien, … , Vijay K. Kuchroo, Stephen D. Miller
Published April 15, 2001
Citation Information: J Clin Invest. 2001;107(8):995-1006. https://doi.org/10.1172/JCI11717.
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Article

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

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.

Authors

Bradley E. Theien, Carol L. Vanderlugt, Todd N. Eagar, Cheryl Nickerson-Nutter, Remederios Nazareno, Vijay K. Kuchroo, Stephen D. Miller

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Preclinical administration of anti–VLA-4 does not inhibit activation of ...
Preclinical administration of anti–VLA-4 does not inhibit activation of peripheral PLP139-151–specific T-cell responses. Splenic lymphocytes from three mice per group were harvested day 13 after immunization and tested for PLP139-151–specific proliferative and Th1 cytokine responses. Three treatments with either anti–VLA-4 or control Ab had been administered by this time point. (a) Viable cells (5 × 105/well) were cultured with the indicated concentrations of PLP139-151 for 4 days. Cultures were pulsed with 3H-TdR 20 hours before harvest. Data are presented as Δ cpm (3H-TdR incorporation in cultures containing peptide antigen, 3H-TdR incorporation in cultures containing medium). Stimulation indices (3H-TdR incorporation in cultures containing peptide antigen, 3H-TdR incorporation in cultures containing medium) are indicated above each bar. 3H-TdR incorporation in cultures containing medium only were 2,849 ± 183 and 8,850 ± 1,227 for control and anti–VLA-4 groups, respectively. IL-2 (b) and IFN-γ (c) levels in the supernatants of cultures harvested at 24 and 48 hours after stimulation with 25 μM of PLP139-151 were determined by ELISA as described in Methods. (d) DTH responses to both the initiating PLP139-151 peptide and the relapse-associated PLP178-191 peptide were evaluated in 4–5 mice treated with either control Ig or anti–VLA-4 at day 36 after immunization. Data represent the mean 24-hour change in ear thickness ± SEM in response to challenge with 10 μg of each peptide. AIL-2 and IFN-γ levels of the PS/2-treated mice were significantly more than those of the control Ig-treated mice; P < 0.01.