Kumari Reena, Palaniyandi Senthilnathan, Hildebrandt Gerhard C
Division of Hematology and Blood and Marrow Transplantation, Markey Cancer Center, University of Kentucky, Lexington, KY, United States.
Front Pharmacol. 2020 Nov 6;11:588449. doi: 10.3389/fphar.2020.588449. eCollection 2020.
Allogeneic hematopoietic stem cell transplantation (HSCT) is the solitary therapeutic therapy for many types of hematological cancers. The benefits of this procedure are challenged by graft vs. host disease (GVHD), causing significant morbidity and mortality. Recent advances in the metabolomics field have revolutionized our understanding of complex human diseases, clinical diagnostics and allow to trace the biosynthesis of metabolites. There is growing evidence for metabolomics playing a role in different aspects of GVHD, and therefore metabolomic reprogramming presents a novel tool for this disease. Pre-transplant cytokine profiles and metabolic status of allogeneic transplant recipients is shown to be linked with a threat of acute GVHD. Immune reactions underlying the pathophysiology of GVHD involve higher proliferation and migration of immune cells to the target site, requiring shifts in energy supply and demand. Metabolic changes and reduced availability of oxygen result in tissue and cellular hypoxia which is extensive enough to trigger transcriptional and translational changes. T cells, major players in acute GVHD pathophysiology, show increased glucose uptake and glycolytic activity. Effector T (Teff) cells activated during nutrient limiting conditions or multiplying during GVHD , depend more on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Dyslipidemia, such as the increase of medium and long chain fatty and polyunsaturated acids in plasma of GVHD patients, has been observed. Sphingolipids associate with inflammatory conditions and cancer. Chronic GVHD (cGVHD) patients show reduced branched-chain amino acids (BCAAs) and increased sulfur-containing metabolites post HSCT. Microbiota-derived metabolites such as aryl hydrocarbon receptor (AhR) ligands, bile acids, plasmalogens and short chain fatty acids vary significantly and affect allogeneic immune responses during acute GVHD. Considering the multitude of possibilities, how altered metabolomics are involved in GVHD biology, multi-timepoints related and multivariable biomarker panels for prognosticating and understanding GVHD are needed. In this review, we will discuss the recent work addressing metabolomics reprogramming to control GVHD in detail.
异基因造血干细胞移植（HSCT）是多种血液系统癌症的唯一治疗方法。该手术的益处受到移植物抗宿主病（GVHD）的挑战，GVHD会导致显著的发病率和死亡率。代谢组学领域的最新进展彻底改变了我们对复杂人类疾病、临床诊断的理解，并有助于追踪代谢物的生物合成。越来越多的证据表明代谢组学在GVHD的不同方面发挥作用，因此代谢组重编程为这种疾病提供了一种新工具。异基因移植受者移植前的细胞因子谱和代谢状态被证明与急性GVHD的威胁有关。GVHD病理生理学背后的免疫反应涉及免疫细胞向靶位点的更高增殖和迁移，这需要能量供需的转变。代谢变化和氧气供应减少导致组织和细胞缺氧，缺氧程度足以引发转录和翻译变化。T细胞是急性GVHD病理生理学的主要参与者，其葡萄糖摄取和糖酵解活性增加。在营养限制条件下激活或在GVHD期间增殖的效应T（Teff）细胞更多地依赖氧化磷酸化（OXPHOS）和脂肪酸氧化（FAO）。已观察到血脂异常，如GVHD患者血浆中中长链脂肪酸和多不饱和脂肪酸增加。鞘脂与炎症和癌症有关。慢性GVHD（cGVHD）患者在HSCT后支链氨基酸（BCAAs）减少，含硫代谢物增加。微生物群衍生的代谢物，如芳烃受体（AhR）配体、胆汁酸、缩醛磷脂和短链脂肪酸有显著差异，并影响急性GVHD期间的异基因免疫反应。考虑到众多可能性，需要多时间点相关和多变量生物标志物面板来预测和理解代谢组学改变如何参与GVHD生物学。在这篇综述中，我们将详细讨论最近关于代谢组重编程以控制GVHD的研究工作。
