The effect of the JAK inhibitor CP-690,550 on peripheral immune parameters in stable kidney allograft patients.
BACKGROUND
CP-690,550 inhibits Janus kinase 3 (JAK3) which mediates signal transduction of receptors of the common gamma-chain cytokines. These cytokines play key roles in lymphocyte function and homeostasis. As part of a phase 1 trial, we evaluated the effect of CP-690,550 on immune parameters.


METHODS
Stable kidney transplant recipients (n=8) receiving mycophenolate mofetil and prednisolone were treated with CP-690,550, 30 mg twice daily orally for 29 days. Blood samples were collected on days 1 (before first dose), 15, 29 (end of treatment), and 57.


RESULTS
Two patients experienced minor infections (one urinary tract infection and one mild respiratory tract infection). Leukocyte counts remained stable, whereas a mean decrease in hemoglobulin of 8% was measured (P=0.01). CP-690,550 treatment for 29 days resulted in statistically significant changes in the number of circulating CD19+ B cells (P=0.05), CD3- CD16+ CD56+ natural killer-cells (P<0.01), and CD4+ CD25bright+ T cells (P=0.05; one-way analysis of variance). After CP-690,550 treatment on day 15 the number of B cells increased by a mean of 100%, (P=0.04), whereas those of natural killer cells and CD4+ CD25bright+ T cells decreased by 65% (P=0.001) and 38% (P=0.03, t test), respectively, from pretreatment baseline. However, the regulatory capacities of the residual CD4+ CD25bright+ T cells remained unchanged pre- and posttreatment. In addition, in the presence of CP-690,550, the interferon-[gamma] production capacity of peripheral blood mononuclear cells was reduced by 39% (median) compared with predose baseline (P=0.01).


CONCLUSIONS
These findings demonstrate the role of JAK3 in the homeostasis and function of select lymphocyte subpopulations. JAK3 inhibition may provide a novel mechanism for the modulation of allogeneic responses in patients after transplantation.
van Gurp
Evelien A F J
EA
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Schoordijk-Verschoor
Wenda
W
Klepper
Mariska
M
Korevaar
Sander S
SS
Chan
Gary
G
Weimar
Willem
W
Baan
Carla C
CC
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006262:Health; D006801:Humans; D007107:Immune System / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D007371:Interferon-gamma; C479163:tofacitinib; D053616:Janus Kinase 3