Dimethyl Fumarate Utilizes Nrf2-Independent and Nrf2-Dependent Pathways For Immune Modulation (S53.006)

Objective: To investigate the role of Nrf2 in DMF-mediated immunomodulation in experimental autoimmune encephalomyelitis (EAE). Background: Oral DMF (dimethyl fumarate) was recently approved for the treatment in the US for relapsing forms of multiple sclerosis (MS). DMF is thought to confer neuroprotection in MS through its inhibition of oxidative stress by activating the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. Recent MS trials demonstrated that DMF effectively reduces relapse rate and development of new MRI demyelinating lesions. Clinical and experimental data suggest that DMF has potent anti-inflammatory properties and promotes immune modulation. Whether these DMF-mediated anti-inflammatory and immunomodulatory effects are mediated by activation of Nrf2, or through Nrf2-independent pathways, is not known. Method: Validation of MMF exposure in various tissues of naive C57BL/6 WT and Nrf2-deficient (Nrf2-/-) mice was conducted after a single dose of DMF (50mg/kg or 100 mg/kg). Blood, spleen and brain were collected 30 min after dosing and analyzed for MMF. As Nrf2-/- mice develop an exacerbated EAE, a new immunization protocol for Nrf2-/- mice was established, which permitted us to systematically dissect effects of DMF in these mice, and to compare findings with those in WT mice. WT and Nrf2-/- mice were immunized with myelin oligodendrocyte glycoprotein (MOG p35-55) and dosed once per day with vehicle or DMF (100 mg/kg) via oral gavage. Results: When compared with WT mice, tissue exposures of MMF were only elevated in Nrf2-/- mice treated with 50mg/kg DMF and comparable between groups receiving 100mg/kg DMF. Upon immunization, preventive administration of DMF protected WT mice from development of EAE, which was accompanied by reduced frequencies of IFN-y and IL-17-producing CD4+ cells. Interestingly, a clear beneficial clinical effect of DMF was also observed in Nrf2-/- mice. Conclusion: These results indicate that Nrf2-independent mechanisms of action play an important role in DMF-mediated immunomodulation during early pathogenic processes of EAE. Disclosure: Dr. Schulze-Topphoff has nothing to disclose. Dr. Varrin-Doyer has nothing to disclose. Dr. Pekarek has nothing to disclose. Dr. Scannevin has received personal compensation for activities with Biogen Idec as an employee. Dr. Scannevin holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Scannevin was involved as an investigator. Dr. Zamvil has received personal compensation for activities with Biogen Idec, Teva Neuroscience, EMD Serono-Pfizer, Novartis, and Genzyme. Dr. Zamvil has received research support from the National Institutes of Health, National Multiple Sclerosis Society, the Maisin Foundation, the Guthy Jackson Charitable Foundation, Teva Neuroscience, and Boehringer-Ingelheim.