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

Dominic C. Borie, Paul S. Changelian, Michael J. Larson, Ming Sing Si, Ricardo Paniagua, John P. Higgins, Bari Holm, Andrew Campbell, Macy Lau, Sally Zhang, Mona G. Flores, Geraldine Rousvoal, Jennifer Hawkins, Douglas A. Ball, Elizabeth M. Kudlacz, William H. Brissette, Eileen A. Elliott, Bruce A. Reitz, Randall E. Morris

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91 Scopus citations

Abstract

Background. Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common chain (γc). Because mutations in genes encoding γc 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.

Original languageEnglish (US)
Pages (from-to)791-801
Number of pages11
JournalTransplantation
Volume79
Issue number7
DOIs
StatePublished - Apr 15 2005

Keywords

  • CP690,550
  • Immunosuppression
  • JAK/STAT
  • JAK3
  • Primates
  • Transplantation

ASJC Scopus subject areas

  • Transplantation

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    Borie, D. C., Changelian, P. S., Larson, M. J., Si, M. S., Paniagua, R., Higgins, J. P., Holm, B., Campbell, A., Lau, M., Zhang, S., Flores, M. G., Rousvoal, G., Hawkins, J., Ball, D. A., Kudlacz, E. M., Brissette, W. H., Elliott, E. A., Reitz, B. A., & Morris, R. E. (2005). Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates. Transplantation, 79(7), 791-801. https://doi.org/10.1097/01.TP.0000157117.30290.6F