Abstract General Information

Title

Reduction of CD8 T lymphocytes in dimethyl fumarate-treated multiple sclerosis patients: Decreased production of IL-2.

Abstract

Background and aim: Dimethyl fumarate (DMF) demonstrated a good safety and tolerability profile in the treatment of relapsing-remitting multiple sclerosis (MS). However, some side effects such as lymphopenia are associated with treatment. Moreover, there is a preferential decrease of CD8+ T cells when compared to CD4+ T cells in MS patients treated with DMF. Here, we investigate the effect of IL-2 in the reduction of CD8 T lymphocytes of DMF-treated MS patients. Methods: The research project was approved by the Ethics Committee, CAAE: 99798918.0.0000.5404. Peripheral blood CD4 and CD8 T lymphocytes and intracellular Caspase 3 from MS patients (n=34) and healthy individuals (n=49) were identified by flow cytometry (FACSymphony A5 BD). Cytokine’s expression was determined by RT-PCR and protein was quantified by ELISA assay. Apoptotic molecules and TTP expression were determined by RT-PCR. Results: We found that there is both a significant reduction of CD8 T lymphocytes subset and decreased production of IL-2 in the peripheral blood of DMF-treated MS patients. The reduction of IL-2 is accompanied by a significant increase of expression of tristetraprolin (TTP), which is an RNA-binding protein that downregulates cytokines at the post-transcriptional level. CD8 T lymphocytes appear to be more sensitive than CD4 T lymphocytes to apoptosis induced by deprivation of IL-2. This was confirmed by the increase in caspase 3 and pro-apoptotic molecules (BAX and BAK) in CD8 T lymphocytes, with a significant reduction in the anti-apoptotic molecule BcL2. Conclusion: IL-2 deprivation induces a more pronounced apoptosis in CD8 T cells subset of MS patients treated with DMF.

Financial support: FAPESP, CAPES and Biogen IDEC