Effect of dimethyl fumarate and monomethyl fumarate in vitro on the profile of myeloid dendritic cells in EAE

Abstract

Multiple Sclerosis (MS) is an autoimmune, chronic and demyelinating disease that affects the Central Nervous System (CNS) of young adults. The oral drug Dimethyl Fumarate (DMF; Dimethyl Fumarate; Tecfidera, Biogen) is a treatment option for relapsing/remitting MS (RRMS). This medicine is converted to its active metabolite, Monomethyl Fumarate (MMF), in the intestine. Despite its beneficial effects, the mechanisms of action of DMF are still not fully elucidated.It is known that regulatory cells, with regulatory T cells (Treg), play an important role in controlling the experimental model of RRMS, Experimental Autoimmune Encephalomyelitis (EAE). The formation of these cells largely depends on the development or not of a tolerogenic profile by local antigen-presenting cells (APCs), such as dendritic cells (DCs). Different subtypes of DCs have been described according to the ability of these cells to induce T cell differentiation. The so-called immunogenic DCs, marked by the expression of CD11c only, would be mature enough to fully activate T lymphocytes, inducing them to a phenotype inflammatory immunogen. On the other hand, tolerogenic DCs, phenotypically identified as being CD11b+ or CD11b+/CD11c+, would be in a less advanced state of maturation, which would give them a lower ability to activate naive T lymphocytes, resulting in the differentiation of these lymphocytes into anti-inflammatory subtypes. , like the Treg.Given the above, it is plausible to assume that the beneficial effect of DMF may come from its action on the DCs development process, or through the modulation of already mature DCs, inducing them, in both cases, to have a tolerogenic character. It is also possible that DMF, after its conversion to MMF, activates the HCAR2 receptor, which is expressed in different cell types, including DCs.With this in mind, in the present IC project, we propose to investigate the effect of DMF and MMF on in vitro generated murine DCs.