Article

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

Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305-5407, and Antibacterials, Inflammation and Immunology, Pfizer Inc., Groton, CT, USA.
Transplantation (impact factor: 4). 12/2005; 80(9):1283-92.
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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Keywords

50% inhibitory concentration
 
acute allograft rejection
 
animals dosed
 
CD8 effector memory T-cell populations
 
Cell surface activation markers expression
 
immune cell phenotype analyzes
 
Janus Kinase
 
natural killer cells activation
 
NK cell
 
organ allograft rejection
 
proliferating cell nuclear antigen expression
 
robust T-cell
 
T-cell proliferative capacities
 
T-cell surface expression
 
T-cells
 
tyrosine kinase essential
 
untransplanted cynomolgus monkeys
 
untransplanted cynos dosed
 
vivo immunomodulatory effects
 
whole blood