Discordant effects of anti–VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis
Bradley E. Theien, Carol L. Vanderlugt, Todd N. Eagar, Cheryl Nickerson-Nutter, Remederios Nazareno, Vijay K. Kuchroo, Stephen D. Miller
Bradley E. Theien, Carol L. Vanderlugt, Todd N. Eagar, Cheryl Nickerson-Nutter, Remederios Nazareno, Vijay K. Kuchroo, Stephen D. Miller
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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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Administration of anti–VLA-4 during ongoing R-EAE enhances infiltration ...
Administration of anti–VLA-4 during ongoing R-EAE enhances infiltration of CD4+ T cells into the CNS and upregulates the expression of VCAM-1. Lower thoracic spinal cord tissue sections from representative animals of the treatment groups described in Figure 1c were examined for infiltration of inflammatory cells on day 33 after immunization. Nine treatments (initiated on day 14) of control Ab or anti–VLA-4 had been given by this time point. Both animals shown had a clinical score of 2. DAPI, in blue, stains all cells; CD4+ cells and VCAM-1 are marked in red. (a) Spinal cord CD4+ infiltrate in a control Ab–treated animal. (b) Spinal cord CD4+ infiltrate in an anti–VLA-4–treated animal. (c) Spinal cord VCAM-1 expression in a control Ab–treated animal. (d) Spinal cord VCAM-1 expression in an anti–VLA-4–treated animal. Tissue from a naive animal was tested simultaneously with all three Ab’s and revealed the presence of only DAPI+ (blue) cells. All sections are 6 μm thick. ×100.