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Sci Rep 2018 Jul 19;8(1):10910

Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways.

Baer A, Colon-Moran W, Bhattarai N

Abstract

Immune responses against gene therapy products limit its therapeutic efficacy and present a safety risk. Identification of agents that blunt immune reactions may aid in developing novel immunomodulatory therapies. Fingolimod (FTY720) is an FDA approved immunomodulatory drug for treating multiple sclerosis that inhibits lymphocyte egress from lymphoid tissues by down regulating sphingosine-1 phosphate receptor (S1PR). Recent studies found that FTY720 inhibits T cell activation (TCA) in a S1PR-independent manner; however, the mechanism is incompletely understood. Here we characterized the effects of FTY720 on human T cell receptor (TCR) signaling pathways. FTY720 inhibited both the TCR-dependent and independent activation of primary human T cells. FTY720 did not affect proximal TCR signaling events as measured by phosphorylation of Lck, ZAP-70 and LAT; however, inhibited PMA/Ionomycin induced distal TCR signaling as measured by IL-2, IFN-¿ release and CD25 expression. FTY720 induced aberrant NFAT1, AP1 and NF¿B activation which were associated with increased acetylation of histone (H3K9). Phosphorylated FTY720 did not inhibit TCA, and arachidonic acid did not rescue FTY720 mediated inhibition of TCA. These data suggest that FTY720 mediated inhibition of TCA is due to inhibition of distal TCR signaling. Understanding FTY720-mediated inhibition of TCA may aid in developing novel FTY720-based immunomodulatory agents.


Category: Journal Article
PubMed ID: #30026610 DOI: 10.1038/s41598-018-29355-0
PubMed Central ID: #PMC6053412
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2018-03-04 Entry Last Modified: 2019-10-27
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