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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Anti–VLA-4 can mediate T-cell costimulation in both cis and trans. Naive...
Anti–VLA-4 can mediate T-cell costimulation in both cis and trans. Naive BALB/c splenic T cells (5 × 104/well) were cultured in 96-well microtiter plates with 5-μm polystyrene sulfate-coated latex microspheres conjugated with the indicated Ab’s as detailed in Methods. Cultures were pulsed with 1 μCi of 3H-TdR at culture initiation and harvested 72 hours later. (a) The concentrations used for the mAbs were: anti-CD3, 0.5 μg/ml; anti-CD28, 20 μg/ml; and anti–VLA-4, 2 μg/ml. The Ab’s were mixed before conjugation to the polystyrene microspheres, and the Ab concentration in all tubes was normalized to a total of 40 μg/ml using hamster control Ig. (b) Anti-CD3 (0.5 μg/ml) and anti-CD28 (20 μg/ml) were conjugated to polystyrene beads. Separate beads were conjugated with the various indicated concentrations of anti–VLA-4. Naive BALB/c splenic T cells (5 × 104/well) were cultured with a combination of the anti-CD3/CD28 + anti–VLA-4 beads in a 1:2 ratio. Hamster Ig–coated beads were added to anti-CD3 and anti-CD3/28 groups to normalize the total number of beads per well. Similar patterns of proliferation were observed in five separate experiments.