Effect of dimethyl fumarate in the evolution of experimental autoimmune encephalomyelitis: ativation of regulatory T cells in intestinal mucosa?

Author(s)

Amanda Dias da Rocha Lima

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2020-03-02

Examining board members

Leonilda Maria Barbosa dos Santos; Enedina Maria Lobato de Oliveira; André Luis Bombeiro

• Advisor: Leonilda Maria Barbosa dos Santos; Fernando Pradella

Abstract

Multiple Sclerosis (MS) is an autoimmune disease of the Central Nervous System (CNS) that mostly affects young women. Experimental Autoimmune Encephalomyelitis (EAE) is a well-established animal model for studying the immunological response of MS. Dimethyl Fumarate (DMF; Tecfidera, Biogen) is an oral medication that was introduced in the last decade as a treatment option for Recurrent Remitting MS (RRMS). DMF is a fumaric acid ester that is hydrolyzed in the gut to Monomethyl Fumarate (MMF), its active metabolite. DMF treatment has been shown to diminish clinical disease activity of MS and EAE. However, the mechanisms of action of DMF are not fully understood. In vitro studies, and some in vivo studies, indicate that DMF can activate the pathway of erythroid nuclear factor 2 related to factor 2 (Nrf2) in the CNS. Another proposed mechanism is the activation of the carboxylic acid receptor (HCAR2) in the microglia, which could inhibit the expression of pro-inflammatory molecules through the inhibition of NF-?B. HCAR2 receptor is found in several cell types, including intestinal epithelial cells (IEC). This study aimed to investigate the effect of DMF administration on the gut mucosal immune response of mice with EAE. C57Bl6 mice were immunized with oligodendrocyte myelin glycoprotein (MOG) 35-55 peptide in complete Freund's adjuvant supplemented with inactivated Mycobacterium tuberculosis. After immunization, the animals were treated twice a day, by gavage, with DMF 7.5 or 30 mg/kg, or with the vehicle. The development of EAE was monitored throughout the treatment. Mesenteric lymph nodes (mLN) and IEC were analyzed by flow cytometry and Reverse Transcription Polymerase Chain Reaction (RT-PCR). The population of CD4+ Foxp3+ regulatory T cells did not present any alterations with the treatment. However, a higher total expression of Foxp3 mRNA was observed with 10 days of DMF administration. The mRNA expression of the anti-inflammatory cytokines IL-10 and IL-27 in mLN was also increased with the DMF 7.5 mg/kg treatment. Additionally, there was no change in the mRNA of the pro-inflammatory cytokines TNF, IL-12a and IFN-?. The expression of IL-17a, IL-4 and IL-2 mRNA was not detected in the mLN of the groups treated with vehicle or DMF. Regarding IEC, an increase was observed in the group treated with DMF 7.5 mg/kg of the CD326+ CD45+ cell population. The results exposed show an anti-inflammatory trend in the intestinal mucosa due to the DMF treatment of EAE. Such an effect can contribute as an additional mechanism of action of DMF in EAE (AU)

• FAPESP's process: 18/03432-2 - Effect of dimethyl fumarate in the evolution of autoimmune experimental encephalomyelitis. activation of Regulatory T cells in intestinal mucosa
• Grantee: Amanda Dias da Rocha Lima
• Support Opportunities: Scholarships in Brazil - Master