Anesthesiology Critical Care Medicine, Children's Hospital Los Angeles, Los Angeles, California.
Department of Pediatric Stem Cell Transplantation, Stanford University School of Medicine, Stanford, California.
Biol Blood Marrow Transplant. 2014 Mar;20(3):361-9. doi: 10.1016/j.bbmt.2013.11.026. Epub 2013 Dec 4.
We mapped the cytokine response to hematopoietic stem cell transplantation (HSCT) by assaying 51 cytokines and chemokines each week for 100 days in 51 children receiving allogeneic (n = 44) or autologous HSCT (n = 7). Assay values were reported as mean fluorescence intensity (MFI). Log transformation converted MFI to clinically relevant measures (ie, pg/mL). We searched for potential markers of transplant complications by using mixed treatment by subject analysis of variance. Global cytokine secretion in HSCT recipients was significantly lower than in concurrent control patients (n = 11). Coincident with the nadir in WBC count, the concentration of many cytokines declined further by the second and third week. All analytes (except monokine induced by gamma interferon [MIG]) subsequently rebounded by week 4 (coincident with engraftment and recovery of WBC count) but often still remained well below control levels. Concurrent with the collective nadir of multiple cytokines, monocyte chemoattractant protein 1 (MCP-1), growth-regulated oncogene alpha (GRO-a), and leptin surged during weeks 2 to 4. High levels of leptin persisted throughout the 100 post-transplant days. Also during weeks 2 to 4, hepatocyte growth factor (HGF) and IL-6 surged in children with complications but not in those without complications. The peak in HGF was more pronounced in veno-occlusive disease (VOD). HGF and IL-6 secretion rose at least 2 weeks before the clinical diagnosis of VOD or graft-versus-host disease (GVHD). From week 4 onward in all groups, the MFI of the cytokine resistin increased to 5 to 15 times above concurrent control. HGF has now emerged in 3 or more biomarker discovery efforts for GVHD (and in our population for VOD as well). HGF (with or without IL-6) should be investigated as a potential predictive biomarker of VOD or GVHD. Alternatively, the hyperinflammatory "signature" provided by a multicytokine assay may be predictive.
我们通过检测 51 名接受同种异体（n=44）或自体造血干细胞移植（n=7）的儿童每周 100 天的 51 种细胞因子和趋化因子，绘制了细胞因子对造血干细胞移植的反应图。测定值以平均荧光强度（MFI）报告。对数转换将 MFI 转换为临床相关指标（即 pg/mL）。我们通过混合治疗对象方差分析寻找移植并发症的潜在标志物。与同期对照组患者（n=11）相比，造血干细胞移植受者的全身细胞因子分泌明显降低。与白细胞计数最低点同时，许多细胞因子的浓度在第二和第三周进一步下降。所有分析物（除干扰素γ诱导的单克隆重组[MIG]外）随后在第 4 周（与植入和白细胞计数恢复同时）反弹，但仍远低于对照水平。与多种细胞因子的集体最低点同时，单核细胞趋化蛋白 1（MCP-1）、生长调节癌基因α（GRO-a）和瘦素在第 2 至 4 周飙升。高水平的瘦素在整个移植后 100 天内持续存在。同样在第 2 至 4 周，有并发症的儿童的肝细胞生长因子（HGF）和白细胞介素 6（IL-6）飙升，但无并发症的儿童则没有。HGF 在静脉闭塞性疾病（VOD）中更为明显。HGF 和 IL-6 的分泌在 VOD 或移植物抗宿主病（GVHD）的临床诊断前至少提前 2 周。在所有组中，从第 4 周开始，细胞因子抵抗素的 MFI 增加到对照的 5 到 15 倍以上。HGF 现已出现在 3 项以上的 GVHD 生物标志物发现研究中（在我们的人群中也出现了 VOD）。HGF（有或没有 IL-6）应作为 VOD 或 GVHD 的潜在预测性生物标志物进行研究。或者，多细胞因子测定提供的过度炎症“特征”可能具有预测性。
