Circulating cell-free mitochondrial DNA as a diagnostic and prognostic biomarker in chronic and late acute graft-versus-host disease in children

线粒体DNA 生物标志物 免疫学 胎儿游离DNA 细胞 生物 寄主(生物学) 移植物抗宿主病 疾病 医学 病理 遗传学 基因 胎儿 怀孕 产前诊断
作者
Shima Azadpour,Sayeh Abdossamadi,Bernard Ng,Elena Ostroumov,Saeid Abroun,Geoffrey D.E. Cuvelier,Kirk R. Schultz
出处
期刊:Experimental Hematology [Elsevier]
卷期号:121: 12-17
标识
DOI:10.1016/j.exphem.2023.02.004
摘要

•Children, similar to adults, have elevated plasma mitochondrial DNA (mtDNA) concentrations at the onset of chronic graft-versus-host disease (cGvHD). •Unlike adults, children have elevations of mtDNA associated only with early-onset cGvHD. •mtDNA elevation appears to be most closely associated with moderate-to-severe cGvHD. •Children have higher mtDNA concentrations on day 100 before the onset of late acute graft-versus-host disease (aGvHD). •mtDNA has a positive correlation between the concentrations of cell-free mtDNA and the mitochondrial metabolites, taurine, and spermine. In an earlier study, we found that mitochondrial DNA (mtDNA) concentration is elevated in adults with chronic graft-versus-host disease (cGvHD), acting as an endogenous source of TLR9 agonists to augment B-cell responses. To validate this in children, we evaluated mtDNA plasma expression in a large pediatric cohort (ABLE/PBMTC 1202 study). Plasma cell-free mtDNA (cf-mtDNA) copy numbers were measured in 202 pediatric patients using quantitative Droplet Digital polymerase chain reaction (ddPCR). Two evaluations were performed: 1) before the onset of cGvHD or late acute graft-versus-host disease (aGvHD) at day 100 ± 14 days and 2) at the time of cGvHD onset compared with time-matched non-cGvHD controls. We found that cf-mtDNA copy numbers were not affected by immune reconstitution post–hematopoietic stem cell transplantation but were higher on day 100 before the onset of late aGvHD and at the onset of cGvHD. We found that cf-mtDNA was not impacted by previous aGvHD, but correlated with the early onset, NIH moderate/severe cGvHD, and did not correlate with other immune cell populations, cytokines, or chemokines but did with the metabolites spermine and taurine. Similar to adults, children have elevated plasma cf-mtDNA concentrations at the early onset of cGvHD, especially in NIH moderate/severe cGvHD, elevation with late aGvHD, and associated with metabolites involved in mitochondrial function. In an earlier study, we found that mitochondrial DNA (mtDNA) concentration is elevated in adults with chronic graft-versus-host disease (cGvHD), acting as an endogenous source of TLR9 agonists to augment B-cell responses. To validate this in children, we evaluated mtDNA plasma expression in a large pediatric cohort (ABLE/PBMTC 1202 study). Plasma cell-free mtDNA (cf-mtDNA) copy numbers were measured in 202 pediatric patients using quantitative Droplet Digital polymerase chain reaction (ddPCR). Two evaluations were performed: 1) before the onset of cGvHD or late acute graft-versus-host disease (aGvHD) at day 100 ± 14 days and 2) at the time of cGvHD onset compared with time-matched non-cGvHD controls. We found that cf-mtDNA copy numbers were not affected by immune reconstitution post–hematopoietic stem cell transplantation but were higher on day 100 before the onset of late aGvHD and at the onset of cGvHD. We found that cf-mtDNA was not impacted by previous aGvHD, but correlated with the early onset, NIH moderate/severe cGvHD, and did not correlate with other immune cell populations, cytokines, or chemokines but did with the metabolites spermine and taurine. Similar to adults, children have elevated plasma cf-mtDNA concentrations at the early onset of cGvHD, especially in NIH moderate/severe cGvHD, elevation with late aGvHD, and associated with metabolites involved in mitochondrial function.
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