Laquinimod Restricts Inflammatory Gene Expression in a Human Model of Reactive Astrogliosis (P02.111)

Abstract

Objective: Laquinimod is an orally administered CNS-active immunomodulator currently in phase III clinical trials for therapy of relapsing remitting multiple sclerosis (RRMS). Data show that RRMS patients show beneficial effects of laquinimod 0.6mg on clinical disease activity as evidenced by slowing of the progression of disability, reducing the rate of MRI-measured brain volume loss, and reducing relapse rate. The current work examines the mechanisms underlying these effects. Background Laquinimod crosses the blood-brain barrier and enters the CNS, thus in addition to peripheral effects it may act directly on CNS-resident lineages including oligodendrocytes, microglia and astrocytes. Increasing evidence implicates reactive astrocytes as critical regulators of CNS inflammation and repair in MS. Design/Methods: Here, we report that laquinimod profoundly impacts proinflammatory gene expression in a human in vitro model of reactive astrogliosis. Results: Interleukin-1beta (IL-1β) is implicated in lesion pathogenesis in RRMS, and in primary human astrocyte cultures it strongly induced inflammatory factors including cytokines, chemokines and reactive nitrogen species. Importantly, at therapeutic concentrations, laquinimod abrogated IL-1β-induced induction of cytokines including tumor necrosis factor-α (TNFα) and IL-6, and inducible nitric oxide synthase. Laquinimod also differentially regulated IL-1β-induced expression of CXC and CC chemokines, suggesting that it acts as an immunomodulator rather than an immunosuppressant in astrocyte cultures. IL-1β exerts its effects via the transcription factor NF-κB, and suggesting mechanism, laquinimod pretreatment of human astrocytes downregulated NF-κB activation. Conclusions: Collectively, these data reveal laquinimod as a regulator of the proinflammatory phenotype in a human model of reactive astrogliosis, and suggest that it may act centrally on resident CNS cells to restrict pathology in MS lesions. Supported by: A research grant from Teva Pharmaceuticals. Disclosure: Dr. Pham has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Hayardeny Nisimov has nothing to disclose. Dr. John has received personal compensation for activities with EMD Serono, Teva Neuroscience, and Biogen Idec. Dr. John has received research support from Teva Neuroscience, and Vaccinex Inc.