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

Abstract

The potent immunomodulator FTY720 elicits immunosuppression via acting on sphingosine 1-phosphate receptors (S1PR), thereby leading to an entrapment of lymphocytes in the secondary lymphoid tissue. To elucidate the potential in vitro effects of this drug on human monocyte-derived DC, we used low nanomolar therapeutic concentrations of FTY720 and phosphorylated FTY720 (FTY720-P) and investigated their influence on DC surface marker expression, protein levels of S1PR and DC effector functions: antigen uptake, chemotaxis, cytokine production, allostimulatory and Thpriming capacity. We report that both FTY720 and FTY720-P reduce chemotaxis of immature and mature DC. Mature DC generated in the presence of FTY720 or FTY720-P showed an impaired immunostimmulatory capacity and reduced IL-12 but increased IL-10 production. T cells cultured in the presence of FTY720-or FTY720-P-treated DC showed an altered cytokine production profile indicating a shift from Th1 toward Th2 differentiation. In treated immature and mature DC, expression levels for two S1PR proteins, S1P 1 and S1P 4, were reduced. We conclude that in vitro treatment with FTY720 affects DC features that are essential for serving their role as antigen-presenting cells. This might represent a new aspect of the overall immunosuppressive action of FTY720 and makes DC potential targets of further sphingolipid-derived drugs.

FTY720 Ameliorates Th1-Mediated Colitis in Mice by Directly Affecting the Functional Activity of CD4+CD25+ Regulatory T Cells

“…Additionally, the disruption of the IL-10 suppressive and regulatory pathway does not allow to relate FTY720 action to differentiation-inducing capacities. Only if this activity of FTY720 could be exerted, an enhanced generation of tolerogenic DC cells might lead to an induction of Treg, which-as mentioned above-has already been suggested in several in vitro studies before (27,28).…”

“…Additionally, S1P modulates the DC-mediated T cell response in favor of Th2 lymphocyte-dominated immunity, i.e., the suppression of IL-12 and enhancement of IL-10 production by S1P-treated DC was associated with a Th1 to Th2 switch of an in vitro primed T cell response (31). To extend these findings regarding S1P toward FTY720 Muller et al (27) clearly showed that in vitro treatment of monocyte-derived DC with therapeutic concentrations of FTY720 and FTY720-P led to a significant change of the cytokine production profile of DC from high IL-12/low IL-10 to low IL-12/high IL-10 production, thus also biasing T cell responses toward Th2 or Treg. This shift from high IL-12/low IL-10 to low IL-12/high IL-10 following treatment with FTY720 indicative for DC targets could also be observed in our in vivo system of TNBS colitis.…”

“…However, in the latter investigation it was also considered that modulation of migration might not be the end of the story regarding its impact on Treg. Indeed, FTY720 may additionally alter the functional activity of Treg directly or via "tolerogenic" DC (25)(26)(27)(28)(29)(30). Thus, a more complex mode of action may be supported by the fact that the affinity profile of FTY720-P on S1PRs is not identical to S1P.…”

Targeting S1P1 Receptor Protects against Murine Immunological Hepatic Injury through Myeloid-Derived Suppressor Cells

“…The number of lymphocytes was reduced in peripheral lymphoid organs but was increased in secondary lymphoid organs, such as the lymph nodes and Peyer's patches (47). However, more recent investigations indicated that the action of FTY720 leads to a significant change in the cytokine-production profile of DCs from IL-12 high IL-10 low to IL-12 low IL-10 high , thus biasing T cell responses toward Th2 cells or Tregs (48). Other recent studies (49,50) showed that a S1P1-directed agonist could dampen CNS inflammation in a plasmacytoid DC-dependent manner.…”

Emerging Therapies for Multiple Sclerosis

“…41 FTY720 also modulates dendritic cell (DC) functions [41][42][43][44] ; among those, DC migration and endocytosis are suppressed via an effect on S1P 3 . 41 Sequestration of lymphocytes in secondary lymphoid organs prevents the cells from trafficking to the tissues target of inflammation.…”