Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts

Transplantation. 2005 Nov 15;80(9):1283-92. doi: 10.1097/01.tp.0000177643.05739.cd.

Abstract

Background: Janus Kinase (JAK) 3 is a tyrosine kinase essential for proper signal transduction downstream of selected cytokine receptors and for robust T-cell and natural killer cells activation and function. JAK3 inhibition with CP-690,550 prevents acute allograft rejection. To provide further insight into the mechanisms of efficacy, we investigated the immunomodulatory effects of CP-690,550 in vitro and in vivo in nonhuman primates.

Methods: Pharmacodynamic assessments of lymphocyte activation, function, proliferation and phenotype were performed in three settings: in vitro in whole blood isolated from untransplanted cynomolgus monkeys (cynos), in vivo in blood from untransplanted cynos dosed with CP-690,550 for 8 days, and in vivo in blood from transplanted cynos immunosuppressed with CP-690,550. Cell surface activation markers expression, IL-2- enhanced IFN-gamma production, lymphocyte proliferation and immune cell phenotype analyzes were performed with multiparametric flow cytometry.

Results: In vitro exposure to CP-690,550 resulted in significant reduction of IL-2-enhanced IFN-gamma production by T-cells (maximum inhibition of 55-63%), T-cell surface expression of CD25 (50% inhibitory concentration (IC50); 0.18 microM) and CD71 (IC50; 1.6 microM), and T-cell proliferative capacities measured by proliferating cell nuclear antigen expression (IC50; 0.87 microM). Similar results were observed in animals dosed with CP-690,550. In addition, transplanted animals displayed significant reduction of NK cell (90% from baseline) and T-cell numbers whereas CD8 effector memory T-cell populations were unaffected.

Conclusions: Potent in vitro and in vivo immunomodulatory effects of the JAK3 inhibitor CP-690,550 likely contribute to its efficacy in the prevention of organ allograft rejection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Immune System / pathology*
  • Immune System / physiology*
  • Interferon-gamma / biosynthesis
  • Interleukin-2 / metabolism
  • Janus Kinase 3
  • Kidney Transplantation / immunology*
  • Killer Cells, Natural / pathology
  • Leukocyte Count
  • Lymphocyte Activation / drug effects
  • Macaca fascicularis
  • Male
  • Piperidines
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrimidines / pharmacology*
  • Pyrroles / pharmacology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology

Substances

  • Interleukin-2
  • Piperidines
  • Pyrimidines
  • Pyrroles
  • Interferon-gamma
  • tofacitinib
  • Protein-Tyrosine Kinases
  • Janus Kinase 3