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

Ricardo Paniagua, Ming Sing Si, Mono G. Flores, Geraldine Rousvoal, Sally Zhang, Oliver Aalami, Andrew Campbell, Paul S. Changelian, Bruce A. Reitz, Dominic C. Borie

Research output: Contribution to journalArticle

68 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1283-1292
Number of pages10
JournalTransplantation
Volume80
Issue number9
DOIs
StatePublished - Nov 2005
Externally publishedYes

Fingerprint

Primates
Allografts
Kidney
Inhibitory Concentration 50
T-Lymphocytes
Population
Natural Killer Cells
Interleukin-2
Janus Kinase 3
Phenotype
Macaca fascicularis
Proliferating Cell Nuclear Antigen
Lymphocyte Activation
tofacitinib
Protein-Tyrosine Kinases
Signal Transduction
Flow Cytometry
Cell Count
Cell Proliferation
Lymphocytes

Keywords

  • CP-690,550
  • Immunosuppression
  • JAK/STAT
  • JAK3
  • Pharmacodynamics
  • Primates
  • Transplantation

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts. / Paniagua, Ricardo; Si, Ming Sing; Flores, Mono G.; Rousvoal, Geraldine; Zhang, Sally; Aalami, Oliver; Campbell, Andrew; Changelian, Paul S.; Reitz, Bruce A.; Borie, Dominic C.

In: Transplantation, Vol. 80, No. 9, 11.2005, p. 1283-1292.

Research output: Contribution to journalArticle

Paniagua, R, Si, MS, Flores, MG, Rousvoal, G, Zhang, S, Aalami, O, Campbell, A, Changelian, PS, Reitz, BA & Borie, DC 2005, 'Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts', Transplantation, vol. 80, no. 9, pp. 1283-1292. https://doi.org/10.1097/01.tp.0000177643.05739.cd
Paniagua, Ricardo ; Si, Ming Sing ; Flores, Mono G. ; Rousvoal, Geraldine ; Zhang, Sally ; Aalami, Oliver ; Campbell, Andrew ; Changelian, Paul S. ; Reitz, Bruce A. ; Borie, Dominic C. / Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts. In: Transplantation. 2005 ; Vol. 80, No. 9. pp. 1283-1292.
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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.",
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AU - Paniagua, Ricardo

AU - Si, Ming Sing

AU - Flores, Mono G.

AU - Rousvoal, Geraldine

AU - Zhang, Sally

AU - Aalami, Oliver

AU - Campbell, Andrew

AU - Changelian, Paul S.

AU - Reitz, Bruce A.

AU - Borie, Dominic C.

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N2 - 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.

AB - 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.

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