The Jak inhibitor CP-690,550 preserves the function of CD4 +CD25brightFoxP3+ regulatory T cells and inhibits effector T cells
The Jak inhibitor CP-690,550 inhibits alloreactivity and is currently being investigated for prevention of allograft rejection after transplantation. In this study, we examined the effect of CP-690,550 on IL-2-mediated Jak/STAT5 phosphorylation by CD4+CD25brightFoxP3 +CD127-/low T cells (Treg) and CD4+CD25 neg effector T cells (Teff) in kidney transplant (KTx) patients. Phosphospecific flow cytometry was used to study the effect of CP-690,550 on IL-2-induced intracellular STAT5-phosphorylation. IL-2-induced phosphorylation of STAT5 (P-STAT5) in both Treg and Teff, which was significantly higher for CD4+CD25bright Treg (increased by 71%, mean) than for CD4+CD25neg Teff (increased by 42%). In the presence of 100 ng/mL CP-690,550, a clinically relevant exposure, IL-2-induced P-STAT5 was partially inhibited in CD4+CD25brightTreg (% inhibition; 51%), while almost completely blocked in Teff (%inhibition; 84%, p = 0.03). The IC50 was 2-3 times higher for Treg (104 ng/mL) than for Teff (40 ng/mL, p = 0.02). In the presence of CP-690,550, Treg exhibited additional suppressive activities on the alloactivated proliferation of Teff (56%, mean). In addition, CD4+CD25bright Treg from KTx-patients receiving CP-690,550 vigorously suppressed the proliferation of Teff (87%, mean). Our findings show that CP-690,550 effectively inhibits Teff function but preserves the suppressive activity of CD4+CD25bright regulatory T cells.
|Keywords||CP-690,550, kidney transplantation, patients, regulatory T cells|
|Persistent URL||dx.doi.org/10.1111/j.1600-6143.2010.03200.x, hdl.handle.net/1765/20476|
Sewgobind, V.D.K.D., Quaedackers, M.E., van der Laan, L.J.W., Kraaijeveld, R., Korevaar, S.S., Chan, G., … Baan, C.C.. (2010). The Jak inhibitor CP-690,550 preserves the function of CD4 +CD25brightFoxP3+ regulatory T cells and inhibits effector T cells. American Journal of Transplantation, 10(8), 1785–1795. doi:10.1111/j.1600-6143.2010.03200.x