Glycolytic metabolism of pathogenic T cells enables early detection of GVHD by 13C-MRI
Glycolytic metabolism of pathogenic T cells enables early detection of GVHD by 13C-MRI
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DOI：
10.1182/blood.2020005770
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发表时间：
2021-01-07
期刊：
影响因子：
20.3
通讯作者：
Buxbaum, Nataliya P.
中科院分区：
文献类型：
--
作者：
Assmann, Julian C.;Farthing, Don E.;Buxbaum, Nataliya P.
移植物抗宿主病（GVHD）是同种异体造血干细胞移植（AHSCT）的一个突出障碍。 GVHD 的确诊是侵入性的，对相关组织进行活检会导致出血和感染的高风险。 T 细胞是 GVHD 发病机制的核心，我们之前对慢性 GVHD 小鼠模型的研究表明，同种异体反应性 CD4(+) T 细胞在出现明显症状之前就流向靶器官。由于糖酵解增加是 T 细胞激活的早期特征，我们假设糖酵解的体内代谢成像将允许在激活的 CD4(+) T 细胞流入器官时对肝脏 GVHD 进行无创检测。事实上，超极化 C-13-丙酮酸磁共振成像在动物出现症状之前检测到肝脏中丙酮酸向乳酸的高转化率，但在随后的明显慢性 GVHD 期间却没有检测到。与此同时，通过转录组、蛋白质、代谢物和离体代谢活性分析，证实CD4(+) T效应记忆细胞（主要致病性CD4(+) T细胞亚群）具有高度糖酵解作用。对接受 AHSCT 的患者循环 T 细胞进行单细胞测序的初步数据也表明，糖酵解增加可能是早期急性 GVHD 的一个特征。代谢成像在医学中的应用越来越多，并且可能在 AHSCT 后的环境中用于 GVHD 的无创早期检测。
Graft-versus-host disease (GVHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (AHSCT). Definitive diagnosis of GVHD is invasive, and biopsies of involved tissues pose a high risk of bleeding and infection. T cells are central to GVHD pathogenesis, and our previous studies in a chronic GVHD mouse model showed that alloreactive CD4(+) T cells traffic to the target organs ahead of overt symptoms. Because increased glycolysis is an early feature of T-cell activation, we hypothesized that in vivo metabolic imaging of glycolysis would allow noninvasive detection of liver GVHD as activated CD4(+) T cells traffic into the organ. Indeed, hyperpolarized C-13-pyruvate magnetic resonance imaging detected high rates of conversion of pyruvate to lactate in the liver ahead of animals becoming symptomatic, but not during subsequent overt chronic GVHD. Concomitantly, CD4(+) T effector memory cells, the predominant pathogenic CD4(+) T-cell subset, were confirmed to be highly glycolytic by transcriptomic, protein, metabolite, and ex vivo metabolic activity analyses. Preliminary data from single-cell sequencing of circulating T cells in patients undergoing AHSCT also suggested that increased glycolysis may be a feature of incipient acute GVHD. Metabolic imaging is being increasingly used in the dinic and may be useful in the post-AHSCT setting for noninvasive early detection of GVHD.