Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor

Jan Thöne, Gisa Ellrichmann, Silvia Seubert, Isabella Peruga, De Hyung Lee, Rebecca Conrad, Liat Hayardeny, Giancarlo Comi, Stefan Wiese, Ralf A. Linker, Ralf Gold

Research output: Contribution to journalArticlepeer-review

Abstract

Laquinimod is a promising, orally available compound that has been successfully evaluated in placebo-controlled phase II/III studies of relapsingremitting multiple sclerosis (MS). Studies are ongoing to further define laquinimod's modulatory mechanisms. Analyses in the animal model of experimental autoimmune encephalomyelitis (EAE) demonstrate that laquinimod reduces infiltration of leukocytes into the central nervous system, induces a Th1 to Th2/3 shift, and suppresses Th17 responses. To evaluate the potential neuroprotective capacity of laquinimod via modulation of brain-derived neurotrophic factor (BDNF), we analyzed the expression of BDNF in blood samples from 203 MS patients treated with laquinimod. Furthermore, we investigated the effect of laquinimod in EAE using a conditional BDNF knockout strain lacking BDNF expression in myeloid cells and T cells (LLF mice). Treatment with laquinimod resulted in a significant and persistent increase in BDNF serum levels of MS patients when compared to baseline and placebo-treated patients. LLF mice treated with laquinimod display a more severe EAE disease course in comparison to wild-type mice. Furthermore, laquinimod-treated wild-type monocytes secreted an anti-inflammatory cytokine pattern in comparison to untreated wild-type monocytes and treated LLF monocytes. Adoptive transfer of laquinimod stimulated monocytes into mice with EAE ameliorated the disease course. Consistent with immunomodulatory properties, laquinimod skewed monocytes toward a regulatory phenotype and also acted via modulation of BDNF, which may contribute to neuroprotection in MS patients.

Original languageEnglish
Pages (from-to)267-274
Number of pages8
JournalAmerican Journal of Pathology
Volume180
Issue number1
DOIs
Publication statusPublished - Jan 2012

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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