1同种异基因造血干细胞移植受者血清白介素 18 水平与急性移植物抗宿主病的关系【摘要】 本研究探讨同种异基因造血干细胞移植(alloHSCT)受者血清白介素 18(IL18)与急性移植物抗宿主病(aGVHD)的关系，查明血清 IL18在 aGVHD 发病中的作用，为临床早期预测aGVHD 提供可靠指标。采用双夹心酶联免疫吸附法(ELISA)检测 62例 alloHSCT患者移植前及移植后 aGVHD 发生前后血清 IL18表达水平。62 例患者被分为 5 组：A 组为无 aGVHD 移植前组（28例） ，指移植后没有发生 aGVHD 的患者在移植前收集的标本;B 组为有 aGVHD 移植前组（ 34 例）, 指移植后发生 aGVHD 的患者在移植前收集的标本;C 组为 aGVHD 症状前组（34 例）, 指临床出现 I-II 级 aGVHD 症状前 3-4 天的标本；然后根据 I-II 级 aGVHD 患者治疗后，有无进展至 III-IV 级回顾性地将 aGVHD 前组患者分为疗效好组（18 例）和疗效差组（16 例）;D 组为 I-II 级 aGVHD 组；E 组为 III-IV 级 aGVHD 组（16 例） 。结果表明： 34 例患者发生 I-II 级 aGVHD，其中 16 例 aGVHD 进展至 III-IV 级；发生 aGVHD患者的血清 IL18表达水平显著高于未发生 aGVHD 患者, 血清IL18表达水平上升发生在 aGVHD 临床症状出现前 3 天左右；血清 IL18表达水平与 aGVHD 的严重程度呈正相关,与 HLA 配型、预处理方案及感染无关；aGVHD 早期血清 IL18表达水平与预后相关；血清 IL18高表达者 aGVHD 容易进展至 IIIIV级。结论： 2血清 IL18 与 aGVHD 的发病相关联, 检测血清 IL18 水平有助于aGVHD 早期诊断，血清 IL18表达水平可作为评估 aGVHD 病情、判断预后的指标。 【关键词】 同种异基因造血干细胞移植 白介素18 急性移植物抗宿主病 早期预测Correlation between Serum Levels of IL18 and Acute Graft Versus Host Disease in Patients after Allogeneic Hematopoietic Stem Cell TransplantationAbstract This study was aimed to investigate the correlation between the serum levels of IL18 and acute graft versus host disease (aGVHD) in patients received allogeneic hematopoietic stem cell transplantation (alloHSCT)， and to explore the role of serum IL18 levels in the pathogenesis of aGVHD so as to provide a reliable and early indicator for the diagnosis of aGVHD. 62 patients received alloHSCT were enrolled in this study. Before and after transplantation, as well as at onset of aGVHD. the serum levels of IL18 were analyzed by ELISA. 62 patients were divided into 5 groups: group A without aGVHD (28 cases) referred to the patients 3who had no aGVHD after transplantation and whose specimen were collected before transplantation; group B with aGVHD before transplantation (34 cases) referred to the patients who had aGVHD after transplantation and whose specimen were collected before transplantation; group C before the onset of aGVHD (34 cases) referred to patients with I-II grade a GVHD whose specimen were collected before 3-4 days, and according to whether the I-II grade aGVHD patients developed III-IV grade or not after treatment, these patients were divided into two subgroups retrospectively, one subgroup had good curative effect ( 18 cases) and the other subgroup had not (16 cases); group D with I-II grade aGVHD; group E with III-IV grade aGVHD (16 cases). The results showed that 34 patients developed I-II grade aGVHD, then out of them 16 patients (16/34) developed III-IV grade aGVHD. The serum levels of IL18 in these patients with aGVHD were higher than that in patients without aGVHD. About 3 days before onset of aGVHD, the serum levels of IL18 started to increase. The serum levels of IL18 were correlated with the severity of aGVHD, but no correlation was found with infection, conditioning regimens and disparity of HLAtyping. The serum levels of IL18 in the 4early stage of aGVHD were correlated with prognosis. The aGVHD of patients with higher serum levels of IL18 easy developed to IIIIV grade aGVHD. It is concluded that the serum level of IL18 in the patients received alloHSCT is related to the occurrence of aGVHD. Detections of serum IL18 are helpful for the early diagnosis of aGVHD, and the serum levels of IL18 may be considered as a reliable indicator to evaluate the prognosis and severity of aGVHD.Key words allogeneic hematopoietic stem cell transplantation; IL18; acute graftversushost disease; early predictionJ Exp Hematol 2007; 15(3):553-557中国实验血液学杂志 J Exp Hematol 2007; 15(3)同种异基因造血干细胞移植受者血清白介素 18 水平和急性移植物抗宿主病的关系 急性移植物抗宿主病（aGVHD ）是同种异基因造血干细胞移植（alloHSCT ）的主要并发症之一。已有的研究表明，aGVHD 发生与细胞因子密切相关1-4 。目前临床上主要根据皮肤、肝脏、胃肠道受累症状的出现和程度对 aGVHD 进行诊断和分级，缺乏直接的免疫学证据，因此需要寻找一种能够直观、实时反映 aGVHD5的免疫学指标。本研究采用双夹心酶联免疫吸附法(ELISA)检测 62例 alloHSCT患者( 其中 HLA 配型不合/单倍型相合的 34 例)移植前及移植后 aGVHD 发生时血清 IL18表达水平，以探讨血清IL18在 aGVHD 发病中的作用，为临床早期诊断 aGVHD 提供可靠指标。至今为止，有关 alloHSCT后血清 IL18水平报道，均为 HLA 全相合单纯 alloBMT或 alloPBSCT受者血清 IL18水平检测结果，我们第一次报道 HLA 配型不合/单倍型相合alloBMT加 alloPBSCT受者血清 IL18水平与 aGVHD 的关系。材料和方法病例62 例 alloHSCT患者为 2004 年 1 月至 2004 年 11 月期间北京大学人民医院血液病研究所骨髓移植病房住院病人, 男 43 例，女19 例，中位年龄 30(9-49)岁。62 例中诊断为急性淋巴细胞白血病(ALL)13 例, 急性髓系白血病(AML)15 例, 慢性髓系白血病(CML)27例, 骨髓增生异常综合征(MDS)3 例,非霍杰金淋巴瘤（NHL）2 例，再生障碍性贫血（AA）1 例，多发性骨髓瘤（MM）1 例。HLA 配型全相合 28 例，HLA 配型不合 34 例，1 个位点不合 4 例,2 个位点不合 18 例,3 个位点不合 12 例。所有患者均签署知情同意书。本研6究选择 34 例 I-II 级 aGVHD 患者（HLA 配型不合和全相合分别为20 和 14 例） ，其中 16 例为 I-II 级进展至 III-IV 级 aGVHD 患者（HLA 配型不合和全相合分别 9 例和 7 例） ，同时选择 28 例无aGVHD 患者作为对比（其中 HLA 配型不合和全相合各 14 例） 。aGVHD 的诊断及分级参照参考文献 5 。62 例患者分为 5 组： A 组为无 aGVHD 移植前组（ 28 例） ，指移植后没有发生 aGVHD的患者在移植前收集的标本; B 组为 aGVHD 移植前组（34 例）, 指移植后发生 aGVHD 的患者在移植前收集的标本; C 组为 aGVHD 症状前组（34 例）, 指临床出现 I-II 级 aGVHD 症状前 3-4 天的标本, 根据 I-II 级 aGVHD 患者治疗后，有无进展至 III-IV 级回顾性将aGVHD 前组患者分为疗效好组（ 18 例）和疗效差组（16 例）; D组为 I-II 级 aGVHD 组； E 组 III-IV 级 aGVHD 组（16 例） 。28 例无 aGVHD 组与 34 例有 aGVHD 组中位年龄无显著差异(P0.05)。另设感染组（24 例） ，是指没有合并 aGVHD 时单纯感染患者的标本。血清标