Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers

This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10 mg twice...

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Vydáno v:Clinical immunology (Orlando, Fla.) Ročník 191; s. 10 - 20
Hlavní autoři: Weinhold, Kent J., Bukowski, Jack F., Brennan, Todd V., Noveck, Robert J., Staats, Janet S., Lin, Liwen, Stempora, Linda, Hammond, Constance, Wouters, Ann, Mojcik, Christopher F., Cheng, John, Collinge, Mark, Jesson, Michael I., Hazra, Anasuya, Biswas, Pinaki, Lan, Shuping, Clark, James D., Hodge, Jennifer A.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier Inc 01.06.2018
Témata:
Adult
Aged
Arthritis, Rheumatoid - drug therapy
Cytotoxicity
Female
Healthy Volunteers
Humans
Interferon-γ
Janus Kinase Inhibitors - pharmacology
Leukocytes - drug effects
Leukocytes - immunology
Lymphocyte Count
Male
Middle Aged
Natural killer cells
Phenotype
Piperidines - adverse effects
Piperidines - pharmacology
Pyrimidines - adverse effects
Pyrimidines - pharmacology
Pyrroles - adverse effects
Pyrroles - pharmacology
T cells
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
Tofacitinib
Cytotoxicity
Healthy volunteers
Natural killer cells
Tofacitinib
T cells
Interferon-γ
ISSN:1521-6616, 1521-7035, 1521-7035
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Shrnutí:This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10 mg twice daily for 4 weeks and were followed for 4 weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naïve and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation (CD)4+, activated naïve CD4+ and effector CD8+ T-cell counts and B-cell counts, normalized 4 weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non-specific T-cell-mediated cytotoxicity and interferon (IFN)-γ production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and IFN-γ production were decreased up to 42% 1 month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4 weeks after withdrawal. •Tofacitinib preferentially targeted activated lymphocytes e.g. CD38+HLA-DR+ T cells.•Ex vivo CMV-specific and non-specific T-cell functional decreases were modest, maximal at day 15, and reversible.•No significant changes were seen in granulocyte count or function, or monocyte count.•Ex vivo NK activity was decreased 1 month after drug withdrawal, the last time point.•No reactivation of latent CMV was observed, as CMV DNA was undetectable in this CMV-seropositive population.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Co-primary authors
ISSN:1521-6616
1521-7035
1521-7035
DOI:10.1016/j.clim.2018.03.002