Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Exp Hematol. 2021 Jun;98:36-46.e2. doi: 10.1016/j.exphem.2021.03.004. Epub 2021 Apr 1.
The objective of this study was to examine the therapeutic effect of ruxolitinib, an orally administered selective Janus kinase (JAK) 1/2 inhibitor, on chronic graft-versus-host disease (cGVHD) using a murine model of sclerodermatous GVHD (scl-GVHD). Compared with scl-GVHD controls, ruxolitinib-treated recipients had scl-GVHD of significantly attenuated clinical and pathological severity in the skin and decreased frequencies of effector cells, CD4 T cells, and CD11b macrophage/monocytes. Regulatory CD4 Foxp3 T cells were expanded whereas interferon-γ (IFN-γ)-producing CD4 T cells were significantly decreased in ruxolitinib-treated recipients. Ruxolitinib suppressed not only the production of IFN-γ from CD4 T cells and monocyte chemoattractant protein 1 (MCP-1) from CD11b macrophage/monocytes, but also the proliferation of these cells in vitro. Levels of both cytokines (IFN-γ and MCP-1) were also reduced in the spleen and skin of ruxolitinib-treated recipients in vivo. IFN-γ-induced MCP-1 production and migration of RAW 264.7 cells, a macrophage cell line, were inhibited by ruxolitinib. However, supplementation with MCP-1 restored this effect of ruxolitinib. In addition, blocking JAK-STAT signaling using ruxolitinib reduced the activation of STAT1 in stimulated immune effector cells. Taken together, these results suggest that ruxolitinib can prevent scl-GVHD by suppressing IFN-γ produced by T cells and MCP-1 expression in macrophage/monocytes via inhibition of JAK-STAT signaling.
本研究旨在通过硬皮病样移植物抗宿主病（scl-GVHD）的小鼠模型，研究口服选择性 Janus 激酶（JAK）1/2 抑制剂芦可替尼（ruxolitinib）对慢性移植物抗宿主病（cGVHD）的治疗效果。与 scl-GVHD 对照组相比，芦可替尼治疗组的皮肤 scl-GVHD 临床和病理严重程度明显减轻，效应细胞、CD4 T 细胞和 CD11b 巨噬细胞/单核细胞的频率降低。调节性 CD4 Foxp3 T 细胞扩增，而芦可替尼治疗组 IFN-γ（IFN-γ）产生的 CD4 T 细胞显著减少。芦可替尼不仅抑制了 CD4 T 细胞产生 IFN-γ和 CD11b 巨噬细胞/单核细胞产生单核细胞趋化蛋白 1（MCP-1），而且还抑制了这些细胞在体外的增殖。在体内，芦可替尼治疗组的脾脏和皮肤中这两种细胞因子（IFN-γ和 MCP-1）的水平也降低了。IFN-γ诱导的 RAW 264.7 细胞（一种巨噬细胞系）MCP-1 产生和迁移被芦可替尼抑制。然而，MCP-1 的补充恢复了芦可替尼的这种作用。此外，使用芦可替尼阻断 JAK-STAT 信号通路可减少刺激免疫效应细胞中 STAT1 的激活。综上所述，这些结果表明，芦可替尼通过抑制 JAK-STAT 信号通路抑制 T 细胞产生 IFN-γ和巨噬细胞/单核细胞中 MCP-1 的表达，可预防 scl-GVHD。
