Kibata Kayoko, Ito Tomoki, Inaba Muneo, Tanaka Akihiro, Iwata Ryoichi, Inagaki-Katashiba Noriko, Phan Vien, Satake Atsushi, Nomura Shosaku
Kansai Medical University, First Department of Internal Medicine, Osaka, Japan.
Kansai Medical University, Department of Neurosurgery, Osaka, Japan.
J Blood Med. 2019 Jul 12;10:217-226. doi: 10.2147/JBM.S206459. eCollection 2019.
Lenalidomide (LEN), an immunomodulatory drug (IMiD), is currently used for treatment of multiple myeloma (MM). LEN potentiates T cell and natural killer cell functions. However, the cellular and molecular mechanisms underlying the immunomodulatory effects of LEN remain unclear. We focused on the effects of LEN on human plasmacytoid dendritic cells (pDCs), which are the major source of interferon (IFN)-α in the blood and play a central role in innate immune responses. We found that bortezomib, a proteasome inhibitor used to treat MM, killed pDCs but that 0.1-3 μM LEN (covering clinical plasma concentration range) did not affect pDC survival or CD86 expression. Bortezomib inhibited pDC-derived IFN-α production in a dose-dependent fashion, but 0.1-3 µM LEN sustained pDC-derived IFN-α production when stimulated with an optimal concentration of CpG-ODN 2216 (3 μM). In pDCs stimulated with a low concentration of CpG-ODN (0.1 μM), LEN enhanced IFN-α production. These results indicated that LEN, when used at a clinically relevant concentration, can potentially enhance IFN-α production by pDCs. Collectively, our findings unveiled a novel target of LEN and extend the repertoire of the drug's known immunomodulatory effects. These effects may explain the low incidence of herpes zoster viral infection observed during LEN treatment compared with bortezomib treatment. LEN may function as an IMiD affecting a wide array of immune cells, including pDCs, leading to amplification of a positive immune axis able to eliminate MM cells.
来那度胺（LEN）是一种免疫调节药物（IMiD），目前用于治疗多发性骨髓瘤（MM）。LEN可增强T细胞和自然杀伤细胞的功能。然而，LEN免疫调节作用的细胞和分子机制仍不清楚。我们重点研究了LEN对人浆细胞样树突状细胞（pDC）的影响，pDC是血液中干扰素（IFN）-α的主要来源，在先天免疫反应中起核心作用。我们发现，用于治疗MM的蛋白酶体抑制剂硼替佐米可杀死pDC，但0.1 - 3 μM的LEN（涵盖临床血浆浓度范围）不影响pDC的存活或CD86表达。硼替佐米以剂量依赖的方式抑制pDC衍生的IFN-α产生，但当用最佳浓度的CpG-ODN 2216（3 μM）刺激时，0.1 - 3 μM的LEN可维持pDC衍生的IFN-α产生。在用低浓度的CpG-ODN（0.1 μM）刺激的pDC中，LEN增强了IFN-α的产生。这些结果表明，LEN在临床相关浓度下使用时，可能会增强pDC产生IFN-α的能力。总体而言，我们的研究结果揭示了LEN的一个新靶点，并扩展了该药物已知的免疫调节作用范围。这些作用可能解释了与硼替佐米治疗相比，LEN治疗期间观察到的带状疱疹病毒感染发生率较低的原因。LEN可能作为一种IMiD发挥作用，影响包括pDC在内的多种免疫细胞，导致能够消除MM细胞的正向免疫轴放大。
