Heine Annkristin, Wolf Anna Maria, Schlaweck Sebastian, Daecke Solveig Nora, Brossart Peter, Wolf Dominik
Department of Oncology, Hematology, Rheumatology and Immune-Oncology, University Hospital Bonn, Bonn, Germany.
Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, University Hospital Innsbruck, Innsbruck, Austria.
Exp Hematol. 2021 Aug;100:37-40. doi: 10.1016/j.exphem.2021.06.004. Epub 2021 Jun 25.
Targeting Janus kinase (JAK) has revolutionized the treatment of myeloproliferative neoplasms. The JAK inhibitor ruxolitinib has improved the outcome and quality of life of patients dramatically at the cost of increased risk of infections. As previously reported, ruxolitinib severely impairs the differentiation of peripheral blood mononuclear cells to monocyte-derived dendritic cells and inhibits the function of dendritic cells in vitro and in vivo, which expanded its use as an immunomodulatory compound. Pacritinib is a novel JAK inhibitor that will soon be approved for the treatment of myeloproliferative neoplasms, and early results are promising. We investigated the impact of the novel JAK inhibitor pacritinib on the function of monocyte-derived dendritic cells and compared it with that of ruxolitinib. In contrast to ruxolitinib, pacritinib exhibits only mild suppressive effects on dendritic cells. The upregulation of activation markers and CCR7 after TLR4 ligation is not or is only marginally affected by pacritinib. Pacritinib, at concentrations reflecting patients' plasma levels, reduces interleukin (IL)-12 secretion, whereas IL-6 and tumor necrosis factor α levels are unchanged at this concentration. In conclusion, the immunosuppressive effect of pacritinib on dendritic cells is significantly less pronounced than the effect of ruxolitinib. Therefore, our data may help to identify those patients with myelofibrosis who may benefit from pacritinib treatment.
靶向 Janus 激酶（JAK）彻底改变了骨髓增殖性肿瘤的治疗方式。JAK 抑制剂芦可替尼显著改善了患者的治疗效果和生活质量，但代价是感染风险增加。如先前报道，芦可替尼严重损害外周血单核细胞向单核细胞衍生树突状细胞的分化，并在体外和体内抑制树突状细胞的功能，这扩大了其作为免疫调节化合物的用途。帕西替尼是一种新型 JAK 抑制剂，即将被批准用于治疗骨髓增殖性肿瘤，早期结果很有前景。我们研究了新型 JAK 抑制剂帕西替尼对单核细胞衍生树突状细胞功能的影响，并将其与芦可替尼进行了比较。与芦可替尼不同，帕西替尼对树突状细胞仅表现出轻微的抑制作用。TLR4 连接后激活标志物和 CCR7 的上调不受帕西替尼影响或仅受到轻微影响。在反映患者血浆水平的浓度下，帕西替尼可降低白细胞介素（IL）-12 的分泌，而在此浓度下 IL-6 和肿瘤坏死因子α水平不变。总之，帕西替尼对树突状细胞的免疫抑制作用明显不如芦可替尼。因此，我们的数据可能有助于确定哪些骨髓纤维化患者可能从帕西替尼治疗中获益。
