INTRODUCTION: 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. MATERIAL: 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.
INTRODUCTION: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. MATERIAL: 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.
Authors: Daniel R Getts; Sushma Shankar; Emily M L Chastain; Aaron Martin; Meghann Teague Getts; Kathryn Wood; Stephen D Miller Journal: Immunotherapy Date: 2011-07 Impact factor: 4.196
Authors: Elisa Piscianz; Erica Valencic; Eva Cuzzoni; Sara De Iudicibus; Elisa De Lorenzo; Giuliana Decorti; Alberto Tommasini Journal: PLoS One Date: 2014-01-09 Impact factor: 3.240