Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19803, USA.
Taconic Biosciences, 1 Discovery Drive, Rensselaer, NY 12144, USA.
Immunotherapy. 2021 Aug;13(12):977-987. doi: 10.2217/imt-2021-0013. Epub 2021 Jun 29.
Graft-versus-host disease (GvHD) is a major complication arising in patients undergoing allogenic hematopoietic stem cell transplantation. We tested ruxolitinib (a selective JAK1/2 inhibitor) efficacy in three different preclinical models of GvHD. Ruxolitinib, at doses that mimic clinically achievable human JAK/signal transducers and activators of transcription target inhibition, significantly reduced alloreactive T-cell activation and infiltration in the lung and skin, leading to improved outcomes in two experimental models of steroid-refractory acute and chronic GvHD. Additionally, we describe a novel humanized GvHD model in which immunodeficient NOG animals are engineered to produce human IL-15 to facilitate enhanced T- and NK cell engraftment, leading to severe GvHD. Ruxolitinib treatment ameliorated disease symptoms resulting from targeted immune modulation via JAK/signal transducers and activators of transcription signaling inhibition.
移植物抗宿主病（GvHD）是异基因造血干细胞移植患者中出现的一种主要并发症。我们在三种不同的 GvHD 临床前模型中测试了鲁索替尼（一种选择性 JAK1/2 抑制剂）的疗效。鲁索替尼的剂量模拟了临床上可达到的人类 JAK/信号转导和转录激活物（STAT）靶标抑制，可显著减少肺和皮肤中同种反应性 T 细胞的激活和浸润，从而改善两种类固醇难治性急性和慢性 GvHD 的实验模型的结果。此外，我们描述了一种新的人源化 GvHD 模型，其中免疫缺陷型 NOG 动物被设计成产生人白细胞介素 15（IL-15），以促进增强的 T 细胞和 NK 细胞植入，导致严重的 GvHD。鲁索替尼治疗通过 JAK/STAT 信号转导抑制靶向免疫调节改善了疾病症状。
