Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China.
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100044, China.
Sci China Life Sci. 2023 Mar;66(3):528-544. doi: 10.1007/s11427-022-2170-2. Epub 2022 Sep 22.
Although glucorticosteroids (GCs) are the standard first-line therapy for acute graft-versus-host disease (aGvHD), nearly 50% of aGvHD patients have no response to GCs. The role of T cell metabolism in murine aGvHD was recently reported. However, whether GCs and metabolism regulators could cooperatively suppress T cell alloreactivity and ameliorate aGvHD remains to be elucidated. Increased glycolysis, characterized by elevated 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and higher rates of glucose consumption and lactate production were found in T cells from aGvHD patients. Genetic upregulation of PFKFB3 induced T cell proliferation and differentiation into proinflammatory cells. In a humanized mouse model, PFKFB3-overexpressing or PFKFB3-silenced T cells aggravated or prevented aGvHD, respectively. Importantly, our integrated data from patient samples in vitro, in a humanized xenogeneic murine model of aGvHD and graft-versus-leukaemia (GVL) demonstrate that GCs combined with a glycolysis inhibitor could cooperatively reduce the alloreactivity of T cells and ameliorate aGvHD without loss of GVL effects. Together, the current study indicated that glycolysis is critical for T cell activation and induction of human aGvHD. Therefore, the regulation of glycolysis offers a potential pathogenesis-oriented therapeutic strategy for aGvHD patients. GCs combined with glycolysis inhibitors promises to be a novel first-line combination therapy for aGvHD patients.
虽然糖皮质激素（GCs）是急性移植物抗宿主病（aGvHD）的标准一线治疗药物，但近 50%的 aGvHD 患者对 GCs 没有反应。最近有研究报道了 T 细胞代谢在鼠类 aGvHD 中的作用。然而，GCs 和代谢调节剂是否可以协同抑制 T 细胞同种异体反应并改善 aGvHD 仍有待阐明。研究发现，aGvHD 患者的 T 细胞中存在糖酵解增加的现象，表现为 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3（PFKFB3）水平升高，葡萄糖消耗和乳酸生成率较高。PFKFB3 的基因上调诱导 T 细胞增殖和向促炎细胞分化。在人源化小鼠模型中，过表达 PFKFB3 或沉默 PFKFB3 的 T 细胞分别加重或预防 aGvHD。重要的是，我们从体外患者样本、aGvHD 和移植物抗白血病（GVL）的人源化异种小鼠模型的综合数据表明，GCs 联合糖酵解抑制剂可以协同降低 T 细胞的同种异体反应性并改善 aGvHD，而不会影响 GVL 效应。总之，本研究表明糖酵解对于 T 细胞激活和诱导人类 aGvHD 至关重要。因此，调节糖酵解为 aGvHD 患者提供了一种潜在的以发病机制为导向的治疗策略。GCs 联合糖酵解抑制剂有望成为 aGvHD 患者的新型一线联合治疗方法。
