Tofacitinib alters monocyte-derived dendritic cell differentiation in rheumatoid arthritis and psoriatic arthritis
Marzaioli Viviana, Canavan Mary, Wade Siobhán , Low Candice, Douglas J. Veale, Fearon Ursula
The Department of Molecular Rheumatology, Trinity College Dublin
Tofacinitib (Pfizer) is an oral Janus kinase inhibitor, recently approved for the treatment of rheumatoid arthritis (RA). An emerging body of literature has investigated the mechanism of action of Tofacinitib in circulating cells, in particular neutrophils and lymphocyte. However, its effect on dendritic cell development has not been yet explored.
The aim of this project is to evaluate the effect of Tofacitinib on inflammatory monocyte-derived dendritic cells (Mo-DC), and in particular on the ability of monocyte to differentiate into dendritic cells, an important step in innate immunity.
Mo-DC were isolated from blood of healthy donor and RA and psoriatic arthritis (PsA) patients by magnetic separation. Monocyte were plated in presence/absence of GM-CSF/IL-4 cocktail for 7 days, to acquire immature dendritic cell phenotype. To evaluate the function of Tofacinitib on Mo-DC differentiation, monocyte were treated with Tofacinitib for 15 minute prior to cytokine stimulation. CD209 (immature DC marker) and CD14 (monocyte marker) were evaluated by flow cytometry in the CD11c positive population.
Tofacinitib inhibited Mo-DC differentiation in both healthy and RA, as shown by reduced CD209 surface marker expression. Interestingly, a decrease in CD209 marker was mirrored by an increase in the monocyte surface marker CD14. In addition, we analysed monocyte from PsA patients and we observed a similar decrease in Mo-DC differentiation, after Tofacinitib treatment. Preliminary data suggest that Tofacinitib also inhibited LPS-induced Mo-DC maturation, reducing CD86, CD80 and CD40 maturation markers.
Together, these observations suggest a novel mechanism of action of Tofacinitib in RA and PsA, by inhibiting Mo-DC development, which may alter migration of DC to the joint and subsequent activation of the immune response. Further studies will evaluate the functional implication of these observations.