We investigated the use of an antisense oligonucleotide (ASO) specific for mRNA of the alpha chain (CD49d) of mouse VLA-4 to down-regulate VLA-4 expression and alter central nervous system (CNS) inflammation. ISIS 17044 potently and specifically reduced CD49d mRNA and protein in cell lines and in ex-vivo-treated primary mouse T cells. When administered prophylactically or therapeutically, ISIS 17044 reduced the incidence and severity of paralytic symptoms in a model of experimental autoimmune encephalomyelitis (EAE). This was accompanied by a significant decrease in the number of VLA-4+ cells, CD4(+) T cells, and macrophages present in spinal cord white matter of EAE mice. ISIS 17044 was found to accumulate in lymphoid tissue of mice, and oligonucleotide was also detected in endothelial cells and macrophage-like cells in the CNS, apparently due to disruption of the blood-brain barrier during EAE. These results demonstrate the potential utility of systemically administered antisense oligonucleotides for the treatment of central nervous system inflammation.