Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses
Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses
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DOI：
10.1182/bloodadvances.2019001410
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发表时间：
2020-08-11
期刊：
影响因子：
7.5
通讯作者：
Nomura, Shosaku
中科院分区：
文献类型：
--
作者：
Phan, Vien;Ito, Tomoki;Nomura, Shosaku
免疫调节药物（IMiD），来那度胺和泊马度胺，广泛用于治疗多发性骨髓瘤;然而，它们偶尔会导致皮肤瘙痒和皮疹发作。在这里，我们分析了IMiDs对人髓样树突状细胞（mDC）作为Th 1或Th 2反应的主要调节因子的影响，以及它们在过敏中所起的作用。我们发现，来那度胺和泊马度胺在临床浓度使用不影响生存或CD 86和OX 40-配体表达的血液树突状细胞响应脂多糖（LPS）和胸腺基质淋巴细胞生成素（TSLP）刺激。来那度胺和泊马度胺均剂量依赖性地抑制白细胞介素-12（IL-12）和TNF的产生以及STAT 4的表达，并增强对LPS的响应中IL-10的产生。当用TSLP刺激时，两种IMiD均显著增强CCL 17产生以及STAT 6和IRF 4表达，并促进记忆性Th 2细胞应答。在46例骨髓瘤患者中，来那度胺相关皮疹发作时的血清CCL 17水平显著高于来那度胺治疗期间和治疗前无皮疹的患者。此外，在来那度胺治疗期间，达到非常好的部分缓解（VGPR）的患者的血清CCL 17水平显著高于低于VGPR的患者。接受来那度胺治疗的患者中，出现皮疹的患者至下一次治疗的中位时间显著长于未出现皮疹的患者。总的来说，IMiD抑制了DC的Th 1诱导能力，而不是促进Th 2应答。因此，来那度胺相关皮疹可能是Th 2轴激活驱动的过敏反应的结果。我们的研究结果表明，IMiDs的临床疗效和副作用皮疹通过免疫刺激密不可分。
Immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, are widely used treatments for multiple myeloma; however, they occasionally lead to episodes of itchy skin and rashes. Here, we analyzed the effects of IMiDs on human myeloid dendritic cells (mDCs) as major regulators of Th1 or Th2 responses and the role they play in allergy. We found that lenalidomide and pomalidomide used at clinical concentrations did not affect the survival or CD86and OX40-ligand expression of blood mDCs in response to lipopolysaccharide (LPS) and thymic stromal lymphopoietin (TSLP) stimulation. Both lenalidomide and pomalidomide dose-dependently inhibited interleukin-12 (IL-12) and TNF production and STAT4 expression, and enhanced IL-10 production in response to LPS. When stimulated with TSLP, both IMiDs significantly enhanced CCL17 production and STAT6 and IRF4 expression and promoted memory Th2-cell responses. In 46 myeloma patients, serum CCL17 levels at the onset of lenalidomide-associated rash were significantly higher than those without rashes during lenalidomide treatment and those before treatment. Furthermore, serum CCL17 levels in patients who achieved a very good partial response (VGPR) were significantly higher compared with a less than VGPR during lenalidomide treatment. The median time to next treatment was significantly longer in lenalidomide-treated patients with rashes than those without. Collectively, IMiDs suppressed the Th1-inducing capacity of DCs, instead promoting a Th2 response. Thus, the lenalidomide-associated rashes might be a result of an allergic response driven by Th2-axis activation. Our findings suggest clinical efficacy and rashes as a side effect of IMiDs are inextricably linked through immunostimulation.