Department of Translational Medicine, Abbott Biotherapeutics, Redwood City, California 94063, USA.
Mult Scler. 2011 Dec;17(12):1441-8. doi: 10.1177/1352458511414755. Epub 2011 Aug 1.
The objective of this study was to evaluate whether interleukin-2 (IL-2) receptor expression on CD56(bright) natural killer (NK) cells predicted CD56(bright) NK cell expansion and therapeutic response to daclizumab (DAC) in multiple sclerosis (MS).
DAC exposure, CD56(bright) NK cell counts, IL-2 receptor alpha (CD25) and beta (CD122) subunits, and new or enlarged lesions on brain MRI were measured in 64 subjects in a pharmacokinetic/pharmacodynamic substudy of the phase 2 CHOICE trial at multiple time points. Peripheral blood mononuclear cell (PBMC) samples were obtained from healthy subjects to assess the relationship among DAC treatment, intermediate affinity IL-2 signaling, and CD56(bright) NK cell expansion.
Increased CD56(bright) NK cell counts in DAC/interferon beta (IFNβ)-treated subjects were observed by day 14, the first post-dosing time point (mean [SD] ln{CD56(bright) NK cell count}: DAC high/IFNβ, 2.01 [1.25]; DAC low/IFNβ, 2.29 [1.06]; placebo/IFNβ, 1.01 [1.03]; adjusted p = 0.003), and persisted throughout the treatment period. Higher DAC dose predicted a faster rate of CD56(bright) NK cell expansion (p < 0.001), but individual subjects' increases in CD56(bright) NK cells from baseline levels were only weakly correlated with DAC exposure (r(2) = 0.167). Higher expression of the intermediate-affinity IL-2 receptor subunit (CD122) on CD56(bright) NK cells at baseline predicted fewer new gadolinium-enhanced (Gd+) lesions during the treatment period (1.77 vs. 0.62 adjusted mean new Gd+ lesions during weeks 8-24, lowest vs. highest quartile of percentage CD122(+) CD56(bright) NK cells; p = 0.033) and a greater increase in CD56(bright) NK cell counts at the end of DAC dosing (p = 0.029).
CD56(bright) NK cell expansion after DAC treatment appears to reflect individual differences in the capacity for intermediate-affinity IL-2 signaling and could provide a basis for predicting clinical response to DAC in MS.
本研究旨在评估白细胞介素-2（IL-2）受体在 CD56（bright）自然杀伤（NK）细胞上的表达是否可预测 CD56（bright）NK 细胞的扩增以及对多发性硬化症（MS）患者的达珠单抗（DAC）治疗的反应。
在 2 期 CHOICE 试验的药代动力学/药效学亚研究中，在多个时间点测量了 64 名受试者的 DAC 暴露量、CD56（bright）NK 细胞计数、IL-2 受体α（CD25）和β（CD122）亚基以及脑 MRI 上新或扩大的病变。从健康受试者中获得外周血单核细胞（PBMC）样本，以评估 DAC 治疗、中亲和力 IL-2 信号传导和 CD56（bright）NK 细胞扩增之间的关系。
在 DAC/干扰素-β（IFNβ）治疗的受试者中，在第 14 天（首次给药后时间点）即可观察到 CD56（bright）NK 细胞计数增加（调整后 ln{CD56（bright）NK 细胞计数}：DAC 高/IFNβ，2.01 [1.25]；DAC 低/IFNβ，2.29 [1.06]；安慰剂/IFNβ，1.01 [1.03]；调整后的 p=0.003），并且在整个治疗期间持续存在。较高的 DAC 剂量预示着 CD56（bright）NK 细胞的扩增速度更快（p<0.001），但个体受试者的 CD56（bright）NK 细胞从基线水平的增加仅与 DAC 暴露量弱相关（r（2）=0.167）。基线时 CD56（bright）NK 细胞上中亲和力 IL-2 受体亚基（CD122）的高表达可预测治疗期间新钆增强（Gd+）病变减少（第 8-24 周时，最低与最高四分位距的调整后新 Gd+病变数分别为 1.77 和 0.62 个；p=0.033），并且在 DAC 给药结束时 CD56（bright）NK 细胞计数的增加更大（p=0.029）。
DAC 治疗后的 CD56（bright）NK 细胞扩增似乎反映了中间亲和力 IL-2 信号转导能力的个体差异，并且可以为预测 DAC 在 MS 中的临床反应提供依据。
