The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells

Area of Science:

• Immunology
• Pharmacology

Background:

• FTY720 is an immunomodulator that causes immunosuppression by targeting sphingosine 1-phosphate receptors (S1PRs).
• FTY720 sequesters lymphocytes in lymphoid tissues, contributing to its immunosuppressive effects.

Purpose of the Study:

• To investigate the in vitro effects of FTY720 and its phosphorylated form (FTY720-P) on human monocyte-derived dendritic cells (DCs).
• To assess the impact of FTY720 on DC surface markers, S1PR protein levels, and effector functions, including antigen uptake, chemotaxis, cytokine production, and T cell priming.

Main Methods:

• Human monocyte-derived DCs were treated with low nanomolar concentrations of FTY720 and FTY720-P.
• Evaluated DC surface marker expression, S1PR protein levels (S1P1 and S1P4), and functional assays like chemotaxis, antigen uptake, and cytokine production.
• Assessed the allostimulatory and T helper (Th)-priming capacity of treated DCs.

Main Results:

• FTY720 and FTY720-P significantly reduced the chemotaxis of both immature and mature DCs.
• Mature DCs treated with FTY720/FTY720-P exhibited impaired immunostimulatory capacity, with decreased IL-12 and increased IL-10 production.
• T cells co-cultured with treated DCs showed altered cytokine profiles, indicating a shift from Th1 to Th2 differentiation.
• Expression of S1PR proteins S1P1 and S1P4 was reduced in FTY720/FTY720-P treated DCs.

Conclusions:

• In vitro FTY720 treatment negatively affects DC functions crucial for antigen presentation.
• FTY720's impact on DCs represents a potential mechanism underlying its overall immunosuppressive action.
• Dendritic cells may serve as targets for FTY720 and other sphingolipid-derived drugs in immunosuppressive therapies.