Contributions
Abstract: P1639
Type: LB Poster
Abstract Category: Late Breaking News
Background: Laquinimod is a novel oral drug currently being evaluated for the treatment of relapsing remitting and primary progressive multiple sclerosis and Huntington Disease. Laquinimod has an effect on the peripheral innate immune system and also acts directly on resident cells within the CNS, especially astrocytes and microglia. To further elucidate laquinimod´s immunomodulatory mechanisms of action we analyzed gene expression levels in laquinimod versus vehicle-treated mice. Transcriptome analysis revealed that laquinimod induces genes downstream to activation of the aryl hydrocarbon receptor (AhR), a pathway that has been shown to play an important role in neuroinflammation.
Goals: In the present study, we investigated whether laquinimod suppresses EAE via the AhR pathway by testing its efficacy in myelin oligodendrocyte glycoprotein (MOG) -induced experimental autoimmune encephalomyelitis (EAE), using AhR knockout (KO) mice.
Methods: MOG35-55 EAE was induced in Wild Type (WT) C57BL/6 and AhR KO (C57BL/6-Ahrtm1.2Arte) mice and animals were treated daily with 25mg/kg laquinimod or vehicle via oral gavage for 30 days. Spleens were removed for gene expression analysis on days 3, 6, 13 and 25, and at study termination spinal cords were removed for histopathological analysis.
Results: Transcriptome analysis revealed that laquinimod (i) reverses the gene expression profile associated with EAE and (ii) induces genes associated with the AhR pathway. The prototypical AhR genes Cyp1a1 and Ahrr were amongst those with the highest average fold change in both naïve and EAE mice treated with laquinimod. We verified the in vivo induction of Cyp1a1 using qPCR of mRNA from livers of treated mice, and also demonstrated that laquinimod is a potent inducer of Cyp1a cultured hepatocytes. This raised the possibility that the therapeutic effect of laquinimod is dependent on AhR activation. Indeed, we report here that the effect of laquinimod was completely lost in MOG-induced EAE in AhR KO mice, as manifested by clinical score and histopathology. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whilst deletion within the CNS partially abrogates the effect of laquinimod in EAE.
Conclusion: These data indicate that deletion of AhR is necessary and sufficient to abrogate the effect of laquinimod in EAE. AhR mainly in the peripheral immune system is the molecular target of laquinimod in this model.
Disclosure: Joel Kaye is an employees of Teva Pharmaceutical Industries, Ltd.
Tal Birnberg is an employee of Teva Pharmaceutical Industries, Ltd.
Tal Hingaly is an employee of Teva Pharmaceutical Industries, Ltd.
Emanuel Raymond is an employee of Teva Pharmaceutical Industries, Ltd.
Rina Kashi is an employee of Teva Pharmaceutical Industries, Ltd.
Victor Piryatinsky is an employee of Teva Pharmaceutical Industries, Ltd.
Aric Orbach is an employee of Teva Pharmaceutical Industries, Ltd.
Iris Grossman is an employee of Teva Pharmaceutical Industries, Ltd.
Volker Knappertz is an employee of Teva Pharmaceutical Industries, Ltd.
Michael R. Hayden is an employee of Teva Pharmaceutical Industries, Ltd.
Ralph Laufer is an employee of Teva Pharmaceutical Industries, Ltd.
Ignacio Caballero is an employee of Immuneering Corporation.
Abstract: P1639
Type: LB Poster
Abstract Category: Late Breaking News
Background: Laquinimod is a novel oral drug currently being evaluated for the treatment of relapsing remitting and primary progressive multiple sclerosis and Huntington Disease. Laquinimod has an effect on the peripheral innate immune system and also acts directly on resident cells within the CNS, especially astrocytes and microglia. To further elucidate laquinimod´s immunomodulatory mechanisms of action we analyzed gene expression levels in laquinimod versus vehicle-treated mice. Transcriptome analysis revealed that laquinimod induces genes downstream to activation of the aryl hydrocarbon receptor (AhR), a pathway that has been shown to play an important role in neuroinflammation.
Goals: In the present study, we investigated whether laquinimod suppresses EAE via the AhR pathway by testing its efficacy in myelin oligodendrocyte glycoprotein (MOG) -induced experimental autoimmune encephalomyelitis (EAE), using AhR knockout (KO) mice.
Methods: MOG35-55 EAE was induced in Wild Type (WT) C57BL/6 and AhR KO (C57BL/6-Ahrtm1.2Arte) mice and animals were treated daily with 25mg/kg laquinimod or vehicle via oral gavage for 30 days. Spleens were removed for gene expression analysis on days 3, 6, 13 and 25, and at study termination spinal cords were removed for histopathological analysis.
Results: Transcriptome analysis revealed that laquinimod (i) reverses the gene expression profile associated with EAE and (ii) induces genes associated with the AhR pathway. The prototypical AhR genes Cyp1a1 and Ahrr were amongst those with the highest average fold change in both naïve and EAE mice treated with laquinimod. We verified the in vivo induction of Cyp1a1 using qPCR of mRNA from livers of treated mice, and also demonstrated that laquinimod is a potent inducer of Cyp1a cultured hepatocytes. This raised the possibility that the therapeutic effect of laquinimod is dependent on AhR activation. Indeed, we report here that the effect of laquinimod was completely lost in MOG-induced EAE in AhR KO mice, as manifested by clinical score and histopathology. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whilst deletion within the CNS partially abrogates the effect of laquinimod in EAE.
Conclusion: These data indicate that deletion of AhR is necessary and sufficient to abrogate the effect of laquinimod in EAE. AhR mainly in the peripheral immune system is the molecular target of laquinimod in this model.
Disclosure: Joel Kaye is an employees of Teva Pharmaceutical Industries, Ltd.
Tal Birnberg is an employee of Teva Pharmaceutical Industries, Ltd.
Tal Hingaly is an employee of Teva Pharmaceutical Industries, Ltd.
Emanuel Raymond is an employee of Teva Pharmaceutical Industries, Ltd.
Rina Kashi is an employee of Teva Pharmaceutical Industries, Ltd.
Victor Piryatinsky is an employee of Teva Pharmaceutical Industries, Ltd.
Aric Orbach is an employee of Teva Pharmaceutical Industries, Ltd.
Iris Grossman is an employee of Teva Pharmaceutical Industries, Ltd.
Volker Knappertz is an employee of Teva Pharmaceutical Industries, Ltd.
Michael R. Hayden is an employee of Teva Pharmaceutical Industries, Ltd.
Ralph Laufer is an employee of Teva Pharmaceutical Industries, Ltd.
Ignacio Caballero is an employee of Immuneering Corporation.