Monitoring of the immunomodulatory effect of CP-690,550 by analysis of the JAK/STAT pathway in kidney transplant patients
BACKGROUND.: The small molecule drug CP-690,550 inhibits Janus kinase 3 at nanomolar concentrations and has recently been shown to prevent allograft rejection in rodents and nonhuman primates. METHODS.: As part of a phase 1 clinical trial, we investigated the effect of CP-690,550 after 29 days of 30 mg twice daily treatment at the cellular level in eight kidney transplant patients by studying ex vivo phosphorylation of STAT5 (P-STAT5), the key substrate of JAK3. RESULTS.: As determined by quantitative fluorescent western blotting, interleukin-2-induced P-STAT5 in YT cells was reduced by a median of 73% (P<0.01) in the presence of serum collected on day 29 compared with pretreatment baseline. When evaluated by phosphospecific flow cytometry, CP-690,550 also reduced interleukin-2-induced P-STAT5 in CD3 (median 20%; P<0.05), CD3CD4 (median 37%; P<0.05), and CD3CD8 (median 34%; P<0.01) populations in patient-derived peripheral blood mononuclear cells. At the functional level, the inhibitory effect of CP-690,550 was confirmed by determining the expression of several STAT5 targets genes. CONCLUSION.: Analysis of P-STAT5 may, therefore, be used to determine the immunomodulatory effect of CP-690,550 at the cellular level in transplant patients.
|Keywords||Immunological monitoring, Immunosuppressive therapy, JAK3 inhibition, Kidney transplantation, Phosphoflow.|
|Persistent URL||dx.doi.org/10.1097/TP.0b013e3181b9ced7, hdl.handle.net/1765/24750|
Quaedackers, M.E., Mol, W.M., Korevaar, S.S., van Gurp, E., van IJcken, W.F.J., Chan, G., … Baan, C.C.. (2009). Monitoring of the immunomodulatory effect of CP-690,550 by analysis of the JAK/STAT pathway in kidney transplant patients. Transplantation, 88(8), 1002–1009. doi:10.1097/TP.0b013e3181b9ced7