title: Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates.
abstract: BACKGROUND
  Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common chain (gammac). Because mutations in genes encoding gammac or JAK3 result in immunodeficiency, we investigated the potential of a rationally designed inhibitor of JAK3, CP-690,550, to prevent renal allograft rejection in nonhuman primates.
  
  
  METHODS
  Life-supporting kidney transplantations were performed between mixed leukocyte reaction-mismatched, ABO blood group-matched cynomolgus monkeys. Animals were treated with CP-690,550 (n = 18) or its vehicle (controls, n = 3) and were euthanized at day 90 or earlier if there was allograft rejection.
  
  
  RESULTS
  Mean survival time (+/- standard error of mean) in animals treated with CP-690,550 (53 +/- 7 days) was significantly longer than in control animals (7 +/- 1 days, P=0.0003) and was positively correlated with exposure to the drug (r = 0.79, P < 0.01). Four treated animals were euthanized at 90 days with a normal renal function and low-grade rejection at final pathology. Occurrence of rejection was significantly delayed in treated animals (46 +/- 7 days from transplantation vs. 7 +/- 1 days in controls, P = 0.0003). Persistent anemia, polyoma virus-like nephritis (n = 2), and urinary calcium carbonate accretions (n = 3) were seen in animals with high exposure. Natural killer cell and CD4 and CD8 T-cell numbers were significantly reduced in treated animals. Blood glucose, serum lipid levels, and arterial blood pressure were within normal range in treated animals, and no cancers were demonstrated.
  
  
  CONCLUSIONS
  CP-690,550 is the first reported JAK3 inhibitor combining efficacy and good tolerability in a preclinical model of allotransplantation in nonhuman primates and thus has interesting potential for immunosuppression in humans.
authors.affiliation: Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. dborie@stanford.edu
authors.forename: Dominic C
authors.initials: DC
authors.lastname: Borie
authors.forename: Paul S
authors.initials: PS
authors.lastname: Changelian
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Larson
authors.forename: Ming-Sing
authors.initials: MS
authors.lastname: Si
authors.forename: Ricardo
authors.initials: R
authors.lastname: Paniagua
authors.forename: John P
authors.initials: JP
authors.lastname: Higgins
authors.forename: Bari
authors.initials: B
authors.lastname: Holm
authors.forename: Andrew
authors.initials: A
authors.lastname: Campbell
authors.forename: Macy
authors.initials: M
authors.lastname: Lau
authors.forename: Sally
authors.initials: S
authors.lastname: Zhang
authors.forename: Mona G
authors.initials: MG
authors.lastname: Flores
authors.forename: Geraldine
authors.initials: G
authors.lastname: Rousvoal
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hawkins
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Ball
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Kudlacz
authors.forename: William H
authors.initials: WH
authors.lastname: Brissette
authors.forename: Eileen A
authors.initials: EA
authors.lastname: Elliott
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Reitz
authors.forename: Randall E
authors.initials: RE
authors.lastname: Morris
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005434:Flow Cytometry; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D053616:Janus Kinase 3; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D016030:Kidney Transplantation / Q000276:immunology*; D007958:Leukocyte Count; D008214:Lymphocytes / Q000276:immunology; D008252:Macaca fascicularis; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C015482:protein kinase modulator; C479163:tofacitinib; D011505:Protein-Tyrosine Kinases; D053616:Janus Kinase 3