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.
Erasmus MC, University Medical Center Rotterdam, Internal Medicine-Transplantation, Rotterdam, The Netherlands.
Monique E
ME
Quaedackers
Wendy
W
Mol
Sander S
SS
Korevaar
Evelien A F J
EA
van Gurp
Wilfred F J
WF
van Ijcken
Gary
G
Chan
Willem
W
Weimar
Carla C
CC
Baan
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008991:Monitoring, Physiologic / Q000379:methods; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D010880:Piperidines; D010919:Placebos; D011239:Prednisolone / Q000627:therapeutic use; D011323:Primates; D011743:Pyrimidines / Q000627:therapeutic use / Q000633:toxicity*; D011758:Pyrroles / Q000627:therapeutic use / Q000633:toxicity*; D012377:Rodentia; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors*; D012449:Safety; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D007166:Immunosuppressive Agents; D010880:Piperidines; D010919:Placebos; D011743:Pyrimidines; D011758:Pyrroles; D050799:STAT5 Transcription Factor; C479163:tofacitinib; D011239:Prednisolone; D053616:Janus Kinase 3; D009173:Mycophenolic Acid