血浆生物标记物水平与儿童急性移植物抗宿主病的相关性

Correlation of the level of plasma biomarkers with acute graft-versus-host disease in children

背景:急性移植物抗宿主病是造血干细胞移植最主要的并发症之一,也是影响移植成败的关键,寻找其特异性生物学标记物对于疾病的早期诊断及治疗尤为重要。婴幼儿时期免疫功能不完善,其急性移植物抗宿主病发生后血浆生物标记物的变化有其自身特点。目的:研究异基因造血干细胞移植儿童患者血浆可溶性生长刺激表达基因2、胰岛再生衍生因子3α、肿瘤坏死因子受体1、白细胞介素6和白细胞介素8水平变化与急性移植物抗宿主病的关系,以期为急性移植物抗宿主病的早期诊断、预测治疗效果和预后提供可靠的检测指标。方法:南方医院儿科2019年3月至2020年12月行异基因造血干细胞移植共计127例患儿,采集移植前10 d、移植后第0,7,14,28,90天、临床急性移植物抗宿主病症状出现时、急性移植物抗宿主病药物干预后1,2,4周患儿外周血,采用Luminex方法检测血清可溶性生长刺激表达基因2、胰岛再生衍生因子3α、肿瘤坏死因子受体1、白细胞介素6和白细胞介素8水平。结果与结论:①在127例患儿中有100例在急性移植物抗宿主病发生点采集血浆标本,按照EBMT-NIH-CIBMTR分级标准未发生急性移植物抗宿主病60例,发生急性移植物抗宿主病有40例,其中有9例Ⅱ-Ⅳ度肠道急性移植物抗宿主病。②急性移植物抗宿主病组发生点的血浆可溶性生长刺激表达基因2和胰岛再生衍生因子3α水平高于无急性移植物抗宿主病组,差异均有显著性意义(P<0.05)。与无急性移植物抗宿主病组相比,急性移植物抗宿主病组移植后7 d的血浆可溶性生长刺激表达基因2水平显著增加(P<0.05)。单纯Ⅱ-Ⅳ度肠道急性移植物抗宿主病组发生点的血浆可溶性生长刺激表达基因2和胰岛再生衍生因子3α水平高于非肠道急性移植物抗宿主病组,差异均有显著性意义(P<0.01;P<0.05)。在发生点和造血干细胞移植后7 d时,急性移植物抗宿主病组和非急性移植物抗宿主病组间肿瘤坏死因子受体1、白细胞介素6和白细胞介素8水平无显著差异(P>0.05)。③在所有急性移植物抗宿主病患者中,与激素敏感组相比,激素耐药组的血浆可溶性生长刺激表达基因2和胰岛再生衍生因子3α水平呈上升趋势。④结果表明,移植后发生点的血浆可溶性生长刺激表达基因2和胰岛再生衍生因子3α水平升高提示急性移植物抗宿主病的发生,二者有助于急性移植物抗宿主病的早期预测。通过分析用药后1,2,4周的生物标记物水平,急性移植物抗宿主病患者治疗后血浆可溶性生长刺激表达基因2和胰岛再生衍生因子3α水平不降低可能与预后不良相关。

BACKGROUND:Acute graft-versus-host disease is one of the major complications of allogeneic hematopoietic stem cell transplantation,and it is also the key to the success of transplantation,which is pa rticularly important to find specific biomarkers of acute graft-versus-host disease for the early diagnosis and treatment.The immune function of children is imperfect,and the changes of plasma biomarkers after acute graft-versus-host disease have their own characteristics.OBJECTIVE:To explo re the correlation of plasma levels of soluble growth stimulation expressed gene 2(sST2),regenerating islet-derived protein 3 alpha(REG3 a),tumor necrosis factor receptor 1(TNFR1),interleukin 6(IL6),and interleukin 8(IL8) with acute graft-versus-host disease in children after allogeneic hematopoietic stem cell transplantation.It is expected to provide reliable detection biomarkers for early diagnosis of acute graft-versus-host disease and prediction of therapy effect and prognosis.METHODS:Samples were collected from 127 pediatric patients who underwent allogeneic hematopoietic stem cell transplantation from March 2019 to December 2020 in the Department of Pediatrics,Nanfang Hospital.The plasma was collected at multiple time points,including 10 days before transplantation,0,7,14,28,and 90 days after transplantation,at the onset of acute graft-versus-host disease symptoms,1,2,and 4 weeks after acute graft-versus-host disease therapy.The plasma concentrations of sST2,REG3α,TNFR1,IL6 and IL8 were detected by the Luminex technology.RESULTS AND CONCLUSION:(1) Plasma samples were collected from 100 of 127 patients at the point of occurrence of acute graft-versus-host disease.Sixty cases never developed acute graft-versus-host disease symptoms;40 cases presented acute graft-versus-host disease,among which 9 cases developed Ⅱ-Ⅳgastrointestinal acute graft-versus-host disease acco rding to EBMT-NIH-CIBMTR classification standard.(2) The plasma concentrations of sST2 and REG3α at onset point in patients were significantly higher in the acute graft-versus-host disease group compared with the non-acute graft-versus-host disease group(P<0.05).sST2 was significantly increased at 7 days after transplantation in the acute graft-versus-host disease group than that in the non-acute graft-versus-host disease group(P <0.05).The sST2 and REG3 a levels were significantly higher in the Ⅱ-Ⅳ gastrointestinal acute graft-versus-host disease group than those in the non-gastrointestinal acute graft-versus-host disease group(P <0.01;P <0.05).There were no significant differences in TNFR1,IL6 and IL8 levels at onset point and 7 days after transplantation in patients between the acute graft-versus-host disease group and the non-acute graft-versus-host disease group(P>0.05).(3) In all acute graft-versus-host disease patients,the plasma concentrations of sST2 and REG3 a in the steroid-resistant acute graft-versus-host disease group showed increasing tendency compared with steroid-sensitive acute graft-versus-host disease group.(4) It is concluded that the increate of plasma sST2 and REG3α levels at onset point after transplantation suggests the incidence of acute graft-versus-host disease.sST2 and REG3α in plasma can be helpful for the early prediction of acute graft-versus-host disease.By analyzing the levels of biomarkers at 1,2,and 4 weeks after treatment,no decrease in the sST2 and REG3α levels in patients with acute graft-versus-host disease after treatment may be related to poor prognosis.