Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
Blood. 2011 Dec 15;118(25):6702-8. doi: 10.1182/blood-2011-08-375006. Epub 2011 Oct 6.
There are no plasma biomarkers specific for GVHD of the gastrointestinal (GI) tract, the GVHD target organ most associated with nonrelapse mortality (NRM) following hematopoietic cell transplantation (HCT). Using an unbiased, large-scale, quantitative proteomic discovery approach to identify candidate biomarkers that were increased in plasma from HCT patients with GI GVHD, 74 proteins were increased at least 2-fold; 5 were of GI origin. We validated the lead candidate, REG3α, by ELISA in samples from 1014 HCT patients from 3 transplantation centers. Plasma REG3α concentrations were 3-fold higher in patients at GI GVHD onset than in all other patients and correlated most closely with lower GI GVHD. REG3α concentrations at GVHD onset predicted response to therapy at 4 weeks, 1-year NRM, and 1-year survival (P ≤ .001). In a multivariate analysis, advanced clinical stage, severe histologic damage, and high REG3α concentrations at GVHD diagnosis independently predicted 1-year NRM, which progressively increased with higher numbers of onset risk factors present: 25% for patients with 0 risk factors to 86% with 3 risk factors present (P < .001). REG3α is a plasma biomarker of GI GVHD that can be combined with clinical stage and histologic grade to improve risk stratification of patients.
目前尚无针对胃肠道（GI）移植物抗宿主病（GVHD）的特异性血浆生物标志物，而 GI-GVHD 是与造血细胞移植（HCT）后非复发死亡率（NRM）最相关的 GVHD 靶器官。本研究采用无偏、大规模、定量蛋白质组学发现方法，旨在鉴定出 HCT 患者发生 GI-GVHD 时血浆中增加的候选生物标志物，结果发现有 74 种蛋白的表达增加了至少 2 倍；其中 5 种蛋白来源于 GI 组织。我们在来自 3 个移植中心的 1014 例 HCT 患者的样本中，通过 ELISA 验证了候选标志物 REG3α。与所有其他患者相比，发生 GI-GVHD 时患者的血浆 REG3α 浓度高 3 倍，与较低的 GI-GVHD 相关性最强。GVHD 发病时的 REG3α 浓度与 4 周时的治疗反应、1 年 NRM 和 1 年生存率密切相关（P ≤.001）。在多变量分析中，晚期临床分期、严重组织学损伤以及 GVHD 诊断时高浓度的 REG3α 均独立预测 1 年 NRM，随着发病危险因素数量的增加，1 年 NRM 逐渐增加：0 个危险因素的患者为 25%，存在 3 个危险因素的患者为 86%（P <.001）。REG3α 是 GI-GVHD 的血浆生物标志物，可与临床分期和组织学分级相结合，改善患者的风险分层。
