Contributions
Abstract: P706
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting MS (RRMS) in 70 countries, with more than 71,000 patients currently being treated worldwide. In the periphery, teriflunomide selectively and reversibly blocks the mitochondrial enzyme dihydroorotate dehydrogenase, limiting the expansion of peripherally activated lymphocytes and thereby reducing the number of these cells available to enter the CNS and mediate inflammatory processes. Teriflunomide is also able to cross the blood-brain barrier and, via a novel mechanism, may directly impact microglia and astrocyte effector functions that contribute to neuroinflammation and neurodegeneration in MS.
Objective: To measure the direct impact of teriflunomide on activated microglia and astrocytes in vitro.
Methods: Primary astrocytes and microglia were isolated from rodent neonatal brains. Cells were pretreated with teriflunomide prior to stimulation with lipopolysaccharide (LPS), or LPS and interferon (IFN) γ, and cell viability was measured. Cytokine production, nitrite production, and phagocytosis were also measured.
Results: Teriflunomide had no impact on the viability of activated primary rodent microglia or astrocytes in vitro. In activated microglia, teriflunomide pretreatment decreased production of the pro-inflammatory mediators, interleukin (IL)-6, IFN γ-induced protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), IL-12p40, and nitrite, and increased production of the anti-inflammatory cytokine IL-10. However, no change was observed in the production of tumour necrosis factor (TNF) or IL-1B. Additionally, there was no effect of teriflunomide on the phagocytic activity of microglia. Pretreatment with teriflunomide also decreased production of the inflammatory mediators, TNF, IL-6, and nitrite, by activated astrocytes.
Conclusions: Teriflunomide treatment can directly impact activated microglia and astrocyte functions in vitro. These data suggest a novel mechanism of action of teriflunomide that may provide neuroprotective effects within the CNS and could contribute to the benefits on clinical outcomes, and the reduction in brain volume loss, observed in patients with RRMS treated with teriflunomide.
Disclosure: Study supported by Sanofi Genzyme.
LW, RA, AM, TG, NH, WS and AE: Employees of Sanofi Genzyme.
Abstract: P706
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting MS (RRMS) in 70 countries, with more than 71,000 patients currently being treated worldwide. In the periphery, teriflunomide selectively and reversibly blocks the mitochondrial enzyme dihydroorotate dehydrogenase, limiting the expansion of peripherally activated lymphocytes and thereby reducing the number of these cells available to enter the CNS and mediate inflammatory processes. Teriflunomide is also able to cross the blood-brain barrier and, via a novel mechanism, may directly impact microglia and astrocyte effector functions that contribute to neuroinflammation and neurodegeneration in MS.
Objective: To measure the direct impact of teriflunomide on activated microglia and astrocytes in vitro.
Methods: Primary astrocytes and microglia were isolated from rodent neonatal brains. Cells were pretreated with teriflunomide prior to stimulation with lipopolysaccharide (LPS), or LPS and interferon (IFN) γ, and cell viability was measured. Cytokine production, nitrite production, and phagocytosis were also measured.
Results: Teriflunomide had no impact on the viability of activated primary rodent microglia or astrocytes in vitro. In activated microglia, teriflunomide pretreatment decreased production of the pro-inflammatory mediators, interleukin (IL)-6, IFN γ-induced protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), IL-12p40, and nitrite, and increased production of the anti-inflammatory cytokine IL-10. However, no change was observed in the production of tumour necrosis factor (TNF) or IL-1B. Additionally, there was no effect of teriflunomide on the phagocytic activity of microglia. Pretreatment with teriflunomide also decreased production of the inflammatory mediators, TNF, IL-6, and nitrite, by activated astrocytes.
Conclusions: Teriflunomide treatment can directly impact activated microglia and astrocyte functions in vitro. These data suggest a novel mechanism of action of teriflunomide that may provide neuroprotective effects within the CNS and could contribute to the benefits on clinical outcomes, and the reduction in brain volume loss, observed in patients with RRMS treated with teriflunomide.
Disclosure: Study supported by Sanofi Genzyme.
LW, RA, AM, TG, NH, WS and AE: Employees of Sanofi Genzyme.