Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.
Department of Statistics, Stanford University, Stanford, CA, United States.
Front Immunol. 2020 Apr 24;11:714. doi: 10.3389/fimmu.2020.00714. eCollection 2020.
Daclizumab beta is a humanized monoclonal antibody that binds to CD25 and selectively inhibits high-affinity IL-2 receptor signaling. As a former treatment for relapsing forms of multiple sclerosis (RMS), daclizumab beta induces robust expansion of the CD56 subpopulation of NK cells that is correlated with the drug's therapeutic effects. As NK cells represent a heterogeneous population of lymphocytes with a range of phenotypes and functions, the goal of this study was to better understand how daclizumab beta altered the NK cell repertoire to provide further insight into the possible mechanism(s) of action in RMS. We used mass cytometry to evaluate expression patterns of NK cell markers and provide a comprehensive assessment of the NK cell repertoire in individuals with RMS treated with daclizumab beta or placebo over the course of 1 year. Treatment with daclizumab beta significantly altered the NK cell repertoire compared to placebo treatment. As previously reported, daclizumab beta significantly increased expression of CD56 on total NK cells. Within the CD56 NK cells, treatment was associated with multiple phenotypic changes, including increased expression of NKG2A and NKp44, and diminished expression of CD244, CD57, and NKp46. These alterations occurred broadly across the CD56 population, and were not associated with a specific subset of CD56 NK cells. While the changes were less dramatic, CD56 NK cells responded distinctly to daclizumab beta treatment, with higher expression of CD2 and NKG2A, and lower expression of FAS-L, HLA-DR, NTB-A, NKp30, and Perforin. Together, these data indicate that the expanded CD56 NK cells share features of both immature and mature NK cells. These findings show that daclizumab beta treatment is associated with unique changes in NK cells that may enhance their ability to kill autoreactive T cells or to exert immunomodulatory functions.
达利珠单抗β是一种人源化单克隆抗体，可与 CD25 结合并选择性抑制高亲和力 IL-2 受体信号传导。作为治疗复发性多发性硬化症（RMS）的前一种治疗方法，达利珠单抗β诱导 CD56 亚群 NK 细胞的强烈扩增，这与药物的治疗效果相关。由于 NK 细胞代表具有一系列表型和功能的淋巴细胞异质性群体，因此本研究的目的是更好地了解达利珠单抗β如何改变 NK 细胞库，以进一步深入了解 RMS 中的可能作用机制。我们使用质谱细胞术评估 NK 细胞标志物的表达模式，并对接受达利珠单抗β或安慰剂治疗的 RMS 患者的 NK 细胞库进行全面评估。与安慰剂治疗相比，达利珠单抗β治疗显着改变了 NK 细胞库。如前所述，达利珠单抗β显着增加了总 NK 细胞上 CD56 的表达。在 CD56 NK 细胞内，治疗与多种表型变化相关，包括 NKG2A 和 NKp44 的表达增加，以及 CD244、CD57 和 NKp46 的表达减少。这些改变广泛发生在 CD56 群体中，与 CD56 NK 细胞的特定亚群无关。虽然变化不那么明显，但 CD56 NK 细胞对达利珠单抗β治疗的反应明显不同，CD2 和 NKG2A 的表达增加，而 FAS-L、HLA-DR、NTB-A、NKp30 和 Perforin 的表达减少。这些数据表明，扩增的 CD56 NK 细胞具有不成熟和成熟 NK 细胞的特征。这些发现表明，达利珠单抗β治疗与 NK 细胞的独特变化相关，这可能增强其杀死自身反应性 T 细胞或发挥免疫调节功能的能力。
