Treatment of experimental autoimmune encephalomyelitis with antisense oligonucleotides against the low affinity neurotrophin receptor

Upregulated expression of the low-affinity neurotrophin receptor (p75) in t he central nervous system (CNS) during experimental autoimmune encephalomye litis (EAE) has recently been demonstrated. To investigate whether p75 play s a role in disease pathogenesis, we adopted a gene therapy approach, utili zing antisense oligonucleotides to downregulate p75 expression during EAE. Phosphorothioate antisense oligonucleotides (AS), nonsense oligonucleotides (NS) or phosphate buffered saline (PBS) were injected daily for 18 days af ter immunization of SJL/J (H-2s)-mice with myelin proteolipid protein (PLP) peptide 139-151. In the AS group, there was a statistically significant re duction in both the mean maximal disease score (1.85 in the AS, 2.94 in the NS and 2.75 in the PBS-groups, respectively, P < 0.025) and in the cumulat ive disease incidence (approximate to 60% in the AS group and approximate t o 90% in the control groups). Histological and immunohistochemical analysis showed reduced inflammation and demyelination, as well as reduced p75 expr ession at the blood-brain barrier (BBB) in the AS-treated mice in compariso n with both control groups. There was no difference, however, in p75 expres sion on neural cells within the CNS between the three groups of mice. We co nclude that p75 could play a proactive role in the pathogenesis of EAE and may exert its effect at the level of the BBB. J. Neurosci. Res. 59:712-721, 2000. (C) 2000 Wiley-Liss, Inc.