他克莫司与巴利昔单抗在肾移植受者中的药效学分析。

Pharmacodynamic analysis of tofacitinib and basiliximab in kidney allograft recipients.

机构信息

Department of Internal Medicine, Erasmus Medical Center, University Hospital Rotterdam, Rotterdam, the Netherlands.

出版信息

Transplantation. 2012 Sep 15;94(5):465-72. doi: 10.1097/TP.0b013e3182626b5a.

DOI:10.1097/TP.0b013e3182626b5a

PMID:22960764

Abstract

BACKGROUND

The common γ-chain (γ(c)) cytokines signal through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and play pivotal roles in lymphocyte activation. We investigated the effect of immunosuppressive drugs targeting this pathway, the JAK inhibitor tofacitinib (CP-690,550) and the anti-interleukin (IL)-2R antibody basiliximab, as part of a phase 2 study.

METHODS

After whole-blood activation with the γ(c) cytokines IL-2, IL-7, and IL-15, STAT5 phosphorylation was determined in T cells of de novo kidney transplantation patients treated with tofacitinib/basiliximab (n=5), calcineurin inhibitor (CNI) (cyclosporine A)/basiliximab (n=4) or CNI (tacrolimus)-based immunosuppression (n=6). The IC(50) for phosphorylated STAT (P-STAT) 5 inhibition by tofacitinib was determined in cytokine-activated CD4(+) and CD8(+) T cells from healthy individuals (n=4).

RESULTS

IC(50) was 26, 72, and 37 ng/mL for IL-2, IL-7, and IL-15 activation, in CD4(+) T cells, respectively; and 35, 61, and 76 ng/mL for IL-2, IL-7, and IL-15 activation, in CD8(+) T cells, respectively. In kidney transplantation patients, 7 days after starting tofacitinib/basiliximab treatment, cytokine-induced P-STAT5 was inhibited in CD4(+) T cells (92% for IL-2 activation, 60% for IL-7, and 75% for IL-15), which persisted for the 2-month study period. In contrast, CNI/basiliximab treatment did not affect IL-7-activated or IL-15-activated P-STAT5; only IL-2-activated P-STAT5 was reduced by 77% on day 7 and recovered to pretreatment levels within 2 months. CD8(+) T cells showed a comparable profile to CD4(+) T cells. P-STAT5 was not inhibited in CNI-treated control patients.

CONCLUSIONS

Tofacitinib therapy strongly inhibits γ(c) cytokine-induced JAK/STAT5 activation, whereas basiliximab suppresses IL-2-stimulated activation only. Pharmacodynamic monitoring offers a unique tool to evaluate the biologic effects of immunosuppressive drugs.

摘要

背景

共同 γ 链（γ(c)）细胞因子通过 Janus 激酶（JAK）-信号转导和转录激活因子（STAT）途径传递信号，并在淋巴细胞激活中发挥关键作用。我们研究了靶向该途径的免疫抑制剂、JAK 抑制剂托法替尼（CP-690,550）和抗白细胞介素（IL）-2R 抗体巴利昔单抗的作用，这是一项 2 期研究的一部分。

方法

在新诊断的肾移植患者的全血激活后，用 IL-2、IL-7 和 IL-15 刺激 γ(c)细胞因子，测定 T 细胞中 STAT5 的磷酸化。用托法替尼/巴利昔单抗（n=5）、钙调神经磷酸酶抑制剂（CNI）（环孢素 A）/巴利昔单抗（n=4）或 CNI（他克莫司）为基础的免疫抑制（n=6）治疗的新诊断肾移植患者的 T 细胞。用健康个体的细胞因子激活的 CD4(+)和 CD8(+)T 细胞（n=4）确定托法替尼对磷酸化 STAT（P-STAT）5 抑制的 IC50。

结果

IC50 分别为 26、72 和 37 ng/ml，用于 CD4(+)T 细胞中 IL-2、IL-7 和 IL-15 的激活；IC50 分别为 35、61 和 76 ng/ml，用于 CD8(+)T 细胞中 IL-2、IL-7 和 IL-15 的激活。在开始托法替尼/巴利昔单抗治疗 7 天后，肾移植患者的细胞因子诱导的 P-STAT5 在 CD4(+)T 细胞中被抑制（IL-2 激活 92%，IL-7 激活 60%，IL-15 激活 75%），并持续了 2 个月的研究期。相比之下，CNI/巴利昔单抗治疗不会影响 IL-7 激活或 IL-15 激活的 P-STAT5；仅 IL-2 激活的 P-STAT5 在第 7 天减少了 77%，并在 2 个月内恢复到预处理水平。CD8(+)T 细胞表现出与 CD4(+)T 细胞相似的特征。CNI 治疗的对照患者中未抑制 P-STAT5。