Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers.
Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers.
复制标题
DOI：
10.1016/j.clim.2018.03.002
复制
发表时间：
2018-06
期刊：
影响因子：
--
通讯作者：
Hodge JA
中科院分区：
文献类型：
--
作者：
Weinhold KJ;Bukowski JF;Brennan TV;Noveck RJ;Staats JS;Lin L;Stempora L;Hammond C;Wouters A;Mojcik CF;Cheng J;Collinge M;Jesson MI;Hazra A;Biswas P;Lan S;Clark JD;Hodge JA
本研究评价了托法替尼治疗对健康志愿者外周血白细胞表型和功能的短期影响，以及停药后任何此类影响的可逆性。巨细胞病毒（CMV）血清阳性受试者接受口服托法替布10 mg每日两次，持续4周，停药后随访4周。托法替尼治疗期间，总淋巴细胞和总T细胞计数轻微增加，B细胞计数增加高达26%。粒细胞或单核细胞计数或粒细胞功能没有显着变化。在治疗期间，幼稚和中枢记忆T细胞计数增加，而所有活化T细胞亚群减少高达69%。除效应记忆分化簇CD 4+以外的T细胞亚群，活化的初始CD 4+和效应CD 8 + T细胞计数和B细胞计数，停药后4周恢复正常。离体活化后，CMV特异性T细胞应答和抗原非特异性T细胞介导的细胞毒性和干扰素（IFN）-γ产生的测量值略有下降。这些T细胞功能变化在第15天最为明显，在仍接受托法替尼治疗时部分恢复正常，停药后恢复至基线水平。总自然杀伤（NK）细胞计数下降33%，停药后恢复至基线水平。在托法替尼治疗期间，NK细胞功能降低，但在测量的参数之间没有一致的时间过程。然而，在停药后1个月，NK细胞介导的细胞毒性、抗体依赖性细胞毒性和IFN-γ产生的标志物降低高达42%。全血中未检测到巨细胞病毒DNA，也没有带状疱疹再激活的病例。未出现新的安全性问题。总之，短期托法替尼治疗对健康CMV+志愿者的白细胞组成和功能的影响是适度的，并且在停药后4周基本可逆。
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 CD4 +, 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 4weeks after withdrawal.
登录
查看更多内容
影响因子：
4.7
作者：
Tanaka, Yoshiya;Suzuki, Makoto;Zwillich, Samuel H.
通讯作者：
Zwillich, Samuel H.
影响因子：
--
作者：
Fleischmann, Roy;Cutolo, Maurizio;Zwillich, Samuel H.
通讯作者：
Zwillich, Samuel H.
影响因子：
2.2
作者：
Richardson, MP;Ayliffe, MJ;Davies, EG
通讯作者：
Davies, EG
影响因子：
--
作者：
Kremer, Joel M.;Bloom, Bradley J.;Zwillich, Samuel H.
通讯作者：
Zwillich, Samuel H.
影响因子：
14.2
作者：
Humblet-Baron, Stephanie;Franckaert, Dean;Liston, Adrian
通讯作者：
Liston, Adrian