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Glycolytic metabolism of pathogenic T cells enables early detection of GVHD by 13C-MRI.

致病性T细胞的糖酵解代谢使得能够通过13C-MRI早期检测GVHD。

  • 影响因子:7.27
  • DOI:10.1182/blood.2020005770
  • 作者列表:"Assmann JC","Farthing DE","Saito K","Maglakelidze N","Oliver B","Warrick KA","Sourbier C","Ricketts CJ","Meyer TJ","Pavletic SZ","Linehan WM","Krishna MC","Gress RE","Buxbaum NP
  • 发表时间:2021-01-07
Abstract

: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 13C-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 clinic and may be useful in the post-AHSCT setting for noninvasive early detection of GVHD.

摘要

: 移植物抗宿主病 (GVHD) 是异基因造血干细胞移植 (AHSCT) 的主要障碍。GVHD的明确诊断是侵入性的,并且受累组织的活组织检查造成出血和感染的高风险。T细胞是GVHD发病机制的核心,我们以前在慢性GVHD小鼠模型中的研究表明,同种异体反应性CD4 + T细胞在明显症状之前运输到靶器官。因为增加的糖酵解是T细胞活化的早期特征,我们假设糖酵解的体内代谢成像将允许在活化的CD4 + T细胞进入器官时无创检测肝脏GVHD。事实上,超极化13c-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期间没有。同时,通过转录组学、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 (主要的致病性CD4 + T细胞亚群) 是高度糖酵解的。来自接受AHSCT的患者循环T细胞的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的特征。代谢成像越来越多地用于临床,并且可能在AHSCT后用于无创性早期检测GVHD的环境中有用。

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