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-γ 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-γ production by T-cells (maximum inhibition of 55-63%), T-cell surface expression of CD25 (50% inhibitory concentration (IC50); 0.18 μM) and CD71 (IC50; 1.6 μM), and T-cell proliferative capacities measured by proliferating cell nuclear antigen expression (IC50; 0.87 μM). 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.
Original language | English (US) |
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Pages (from-to) | 1283-1292 |
Number of pages | 10 |
Journal | Transplantation |
Volume | 80 |
Issue number | 9 |
DOIs | |
State | Published - Nov 2005 |
Keywords
- CP-690,550
- Immunosuppression
- JAK/STAT
- JAK3
- Pharmacodynamics
- Primates
- Transplantation
ASJC Scopus subject areas
- Transplantation