Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts.
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.
Paniagua
Ricardo
R
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.
Si
Ming-Sing
MS
Flores
Mona G
MG
Rousvoal
Geraldine
G
Zhang
Sally
S
Aalami
Oliver
O
Campbell
Andrew
A
Changelian
Paul S
PS
Reitz
Bruce A
BA
Borie
Dominic C
DC
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D007107:Immune System / Q000473:pathology* / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000378:metabolism; D053616:Janus Kinase 3; D016030:Kidney Transplantation / Q000276:immunology*; D007694:Killer Cells, Natural / Q000473:pathology; D007958:Leukocyte Count; D008213:Lymphocyte Activation / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D007376:Interleukin-2; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D007371:Interferon-gamma; C479163:tofacitinib; D011505:Protein-Tyrosine Kinases; D053616:Janus Kinase 3