872:
EFFECT OF TOFACITINIB ON IGE-MEDIATED DEGRANULATION OF LAD2 HUMAN MAST CELLS AND PGD2 PRODUCTION
Monday, March 5, 2018
South Hall A2 (Convention Center)
Arnold Kirshenbaum, MD FAAAAI, Yun Bai, MS, Dean D. Metcalfe, MD, FAAAAI
RATIONALE: Tofacitinib is an inhibitor of the enzymes JAK1 and JAK3, and can interfere with the JAK-STAT signaling pathway, transmission of extracellular information into the cell nucleus and DNA transcription. Tofacitinib is approved for use in rheumatoid arthritis and is being explored for use in psoriasis, colitis, atopic dermatitis and ankylosing spondylitis. Recently, tofacitinib was said to lead to symptomatic improvement in two patients diagnosed with mast cell activation syndrome. This prompted us to examine the effect of tofacitinib on the biologic reactivity of the human mast cell line, LAD2.

METHODS: In preliminary experiments, cultured LAD2 cells were incubated overnight with biotinylated human IgE. Cells were washed and then incubated with 1, 10, 100, 1000 nM tofacitinib for 1 hour. FcepsilonRI crosslinking was next performed with streptavidin, and degranulation monitored by the release of beta-hexosaminidase (b-Hex). LAD2 cells were also incubated with tofacitinib followed by stimulation with PMA, degranulation and release of b-Hex. The effect on PgD2 production was measured 30 minutes following IgE mediated mast cell activation.

RESULTS: In LAD2 cells, b-Hex release following FcepsilonRI crosslinking or PMA stimulation remained consistently high (50-60%) in the presence of tofacitinib with no dose-response reduction in degranulation. Similarly, tofacitinib had no effect on PgD2 release.

CONCLUSIONS: The JAK kinase inhibitor tofacitinib had no effect on LAD2 human mast cell degranulation or PgD2 production. Additional experiments are underway including an examination of the effects of tofacitinib on LAD2 cytokine production, adhesion and proliferation.