title: Pharmacodynamic analysis of tofacitinib and basiliximab in kidney allograft recipients.
abstract: BACKGROUND
  The common γ-chain (γ(c)) cytokines signal through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and play pivotal roles in lymphocyte activation. We investigated the effect of immunosuppressive drugs targeting this pathway, the JAK inhibitor tofacitinib (CP-690,550) and the anti-interleukin (IL)-2R antibody basiliximab, as part of a phase 2 study.
  
  
  METHODS
  After whole-blood activation with the γ(c) cytokines IL-2, IL-7, and IL-15, STAT5 phosphorylation was determined in T cells of de novo kidney transplantation patients treated with tofacitinib/basiliximab (n=5), calcineurin inhibitor (CNI) (cyclosporine A)/basiliximab (n=4) or CNI (tacrolimus)-based immunosuppression (n=6). The IC(50) for phosphorylated STAT (P-STAT) 5 inhibition by tofacitinib was determined in cytokine-activated CD4(+) and CD8(+) T cells from healthy individuals (n=4).
  
  
  RESULTS
  IC(50) was 26, 72, and 37 ng/mL for IL-2, IL-7, and IL-15 activation, in CD4(+) T cells, respectively; and 35, 61, and 76 ng/mL for IL-2, IL-7, and IL-15 activation, in CD8(+) T cells, respectively. In kidney transplantation patients, 7 days after starting tofacitinib/basiliximab treatment, cytokine-induced P-STAT5 was inhibited in CD4(+) T cells (92% for IL-2 activation, 60% for IL-7, and 75% for IL-15), which persisted for the 2-month study period. In contrast, CNI/basiliximab treatment did not affect IL-7-activated or IL-15-activated P-STAT5; only IL-2-activated P-STAT5 was reduced by 77% on day 7 and recovered to pretreatment levels within 2 months. CD8(+) T cells showed a comparable profile to CD4(+) T cells. P-STAT5 was not inhibited in CNI-treated control patients.
  
  
  CONCLUSIONS
  Tofacitinib therapy strongly inhibits γ(c) cytokine-induced JAK/STAT5 activation, whereas basiliximab suppresses IL-2-stimulated activation only. Pharmacodynamic monitoring offers a unique tool to evaluate the biologic effects of immunosuppressive drugs.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, University Hospital Rotterdam, Rotterdam, the Netherlands. r.vafadari@erasmusmc.nl
authors.forename: Ramin
authors.initials: R
authors.lastname: Vafadari
authors.forename: Monique E
authors.initials: ME
authors.lastname: Quaedackers
authors.forename: Marcia M
authors.initials: MM
authors.lastname: Kho
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Mol
authors.forename: Gary
authors.initials: G
authors.lastname: Chan
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000077552:Basiliximab; D016572:Cyclosporine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D019409:Interleukin-15 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D009426:Netherlands; D010766:Phosphorylation; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016559:Tacrolimus / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D016572:Cyclosporine; C479163:tofacitinib; D000077552:Basiliximab; D053612:Janus Kinases; D016559:Tacrolimus