Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Department of Experimental Pharmacology and Translational Science, Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A., Parma, Italy.
J Transl Med. 2022 May 10;20(1):203. doi: 10.1186/s12967-022-03402-x.
Tanimilast is a novel and selective inhaled inhibitor of phosphodiesterase-4 in advanced clinical development for chronic obstructive pulmonary disease (COPD). Tanimilast is known to exert prominent anti-inflammatory activity when tested in preclinical experimental models as well as in human clinical studies. Recently, we have demonstrated that it also finely tunes, rather than suppressing, the cytokine network secreted by activated dendritic cells (DCs). This study was designed to characterize the effects of tanimilast on T-cell polarizing properties of DCs and to investigate additional functional and phenotypical features induced by tanimilast.
DCs at day 6 of culture were stimulated with LPS in the presence or absence of tanimilast or the control drug budesonide. After 24 h, DCs were analyzed for the expression of surface markers of maturation and activation by flow cytometry and cocultured with T cells to investigate cell proliferation and activation/polarization. The regulation of type 2-skewing mediators was investigated by real-time PCR in DCs and compared to results obtained in vivo in a randomized placebo-controlled trial on COPD patients treated with tanimilast.
Our results show that both tanimilast and budesonide reduced the production of the immunostimulatory cytokine IFN-γ by CD4 T cells. However, the two drugs acted at different levels since budesonide mainly blocked T cell proliferation, while tanimilast skewed T cells towards a Th2 phenotype without affecting cell proliferation. In addition, only DCs matured in the presence of tanimilast displayed increased CD86/CD80 ratio and CD141 expression, which correlated with Th2 T cell induction and dead cell uptake respectively. These cells also upregulated cAMP-dependent immunosuppressive molecules such as IDO1, TSP1, VEGF-A and Amphiregulin. Notably, the translational value of these data was confirmed by the finding that these same genes were upregulated also in sputum cells of COPD patients treated with tanimilast as add-on to inhaled glucocorticoids and bronchodilators.
Taken together, these findings demonstrate distinct immunomodulatory properties of tanimilast associated with a type 2 endotype and CD141 upregulation in DCs and provide a mechanistic rationale for the administration of tanimilast on top of inhaled corticosteroids.
Tanimilast 是一种新型、选择性磷酸二酯酶-4 抑制剂，目前已进入慢性阻塞性肺疾病（COPD）的临床开发后期。在临床前实验模型和人体临床研究中，Tanimilast 表现出显著的抗炎活性。最近，我们已经证明它还可以精细调节（而非抑制）激活树突状细胞（DC）分泌的细胞因子网络。本研究旨在研究 Tanimilast 对 DC 调节 T 细胞极化特性的影响，并研究 Tanimilast 诱导的其他功能和表型特征。
培养第 6 天的 DC 用 LPS 刺激，同时存在或不存在 Tanimilast 或对照药物布地奈德。24 小时后，通过流式细胞术分析 DC 表面成熟和激活标志物的表达，并与 T 细胞共培养，以研究细胞增殖和激活/极化。通过实时 PCR 研究 DC 中 2 型偏向调节因子的表达，并与 COPD 患者接受 Tanimilast 治疗的随机安慰剂对照试验中的体内结果进行比较。
我们的结果表明，Tanimilast 和布地奈德均可减少 CD4 T 细胞产生免疫刺激性细胞因子 IFN-γ。然而，两种药物作用于不同的水平，因为布地奈德主要阻断 T 细胞增殖，而 Tanimilast 则使 T 细胞向 Th2 表型倾斜，而不影响细胞增殖。此外，只有在 Tanimilast 存在下成熟的 DC 显示出 CD86/CD80 比值和 CD141 表达增加，这分别与 Th2 T 细胞诱导和死细胞摄取相关。这些细胞还上调了 cAMP 依赖性免疫抑制分子，如 IDO1、TSP1、VEGF-A 和 Amphiregulin。值得注意的是，这些数据的转化价值得到了 COPD 患者痰细胞中这些相同基因上调的证实，这些患者在吸入糖皮质激素和支气管扩张剂的基础上接受 Tanimilast 治疗。
综上所述，这些发现表明 Tanimilast 具有独特的免疫调节特性，与 2 型表型和 DC 中 CD141 上调相关，并为在吸入皮质激素的基础上使用 Tanimilast 提供了机制上的依据。
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