Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates

Transplantation. 2005 Apr 15;79(7):791-801. doi: 10.1097/01.tp.0000157117.30290.6f.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Tolerance
  • Flow Cytometry
  • Graft Rejection / drug therapy*
  • Graft Rejection / immunology
  • Graft Survival / drug effects*
  • Graft Survival / immunology
  • Immunosuppression
  • Immunosuppressive Agents / pharmacology*
  • Immunosuppressive Agents / therapeutic use
  • Intracellular Signaling Peptides and Proteins / pharmacology*
  • Intracellular Signaling Peptides and Proteins / therapeutic use
  • Janus Kinase 3
  • Kidney / drug effects
  • Kidney / physiopathology
  • Kidney Transplantation / immunology*
  • Leukocyte Count
  • Lymphocytes / immunology
  • Macaca fascicularis
  • Piperidines
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Pyrroles / administration & dosage
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology*
  • Pyrroles / therapeutic use
  • Time Factors
  • Transplantation, Homologous

Substances

  • Immunosuppressive Agents
  • Intracellular Signaling Peptides and Proteins
  • Piperidines
  • Pyrimidines
  • Pyrroles
  • protein kinase modulator
  • tofacitinib
  • Protein-Tyrosine Kinases
  • Janus Kinase 3