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中华移植杂志(电子版)

中华移植杂志(电子版) ›› 2025, Vol. 19 ›› Issue (04) : 237 -242. doi: 10.3877/cma.j.issn.1674-3903.2025.04.005

论著

急性移植物抗宿主病相关特异性血清生物标志物分析
刘恒1, 吴涛1,†(), 鱼玲玲1, 葸瑞1, 潘耀柱1, 毛东锋1, 石亚军1, 刘文慧1, 田红娟1, 王莹1, 张晓菲1, 张曦2   
  1. 1730050　兰州，中国人民解放军联勤保障部队第九四〇医院（原兰州军区兰州总医院）全军血液病中心
    2400037　重庆，陆军军医大学第二附属医院血液病医学中心
  • 收稿日期:2025-04-25 出版日期:2025-08-25
  • 通信作者: 吴涛
  • 基金资助:
    甘肃省创新基地和人才计划(21JR7RA015); 甘肃省重点研发计划(22YF7FA106); 兰州市青年科技人才创新项目(2023-QN-16); 联勤保障部队第九四〇医院血液病医学研究中心项目(2021yxky078)

Analysis of specific serum biomarkers associated with acute graft versus host disease

Heng Liu1, Tao Wu1,†(), Lingling Yu1, Rui Xi1, Yaozhu Pan1, Dongfeng Mao1, Yajun Shi1, Wenhui Liu1, Hongjuan Tian1, Ying Wang1, Xiaofei Zhang1, Xi Zhang2   

  1. 1Department of Hematology, the 940th Hospital of Joint Logistic Support Force of PLA, Lanzhou 730050, China
    2Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing 400037, China
  • Received:2025-04-25 Published:2025-08-25
  • Corresponding author: Tao Wu
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刘恒, 吴涛, 鱼玲玲, 葸瑞, 潘耀柱, 毛东锋, 石亚军, 刘文慧, 田红娟, 王莹, 张晓菲, 张曦. 急性移植物抗宿主病相关特异性血清生物标志物分析[J/OL]. 中华移植杂志(电子版), 2025, 19(04): 237-242.

Heng Liu, Tao Wu, Lingling Yu, Rui Xi, Yaozhu Pan, Dongfeng Mao, Yajun Shi, Wenhui Liu, Hongjuan Tian, Ying Wang, Xiaofei Zhang, Xi Zhang. Analysis of specific serum biomarkers associated with acute graft versus host disease[J/OL]. Chinese Journal of Transplantation(Electronic Edition), 2025, 19(04): 237-242.

目的

探讨血清生物标志物IL-6、IL-8、可溶性肿瘤坏死因子受体1(sTNFR1)、再生胰岛衍生蛋白3α(Reg3α)、可溶性肿瘤发生抑制蛋白2(sST2)、弹性蛋白酶抑制因子(elafin)与异基因造血干细胞移植(allo-HSCT)后急性移植物抗宿主病(aGVHD)相关性。

方法

回顾性分析2019年1月至2023年1月于中国人民解放军联勤保障部队第九四〇医院血液科接受allo-HSCT的106例患者临床资料。其中发生aGVHD的49例患者纳入aGVHD组，未发生aGVHD的57例患者纳入无aGVHD组。所有患者均于移植后＋28、＋56和＋90 d采集外周血进行细胞因子检测。正态分布计量资料组间比较采用独立样本t检验；不符合正态分布的计量资料组间比较采用Mann-Whitney U检验。计数资料组间比较采用卡方检验。P<0.05为差异有统计学意义。

结果

移植后＋28 d时，无aGVHD组患者sST2水平[52.2(34.9～93.0)pg/mL]低于aGVHD组[98.2(58.3～186.7)pg/mL]，差异有统计学意义(Z＝－3.268，P<0.05)；＋56 d时，无aGVHD组患者sTNFR1、sST2和Reg3α水平分别为1 971.2(1 656.8～2 537.0)、76.4(40.0～134.4)和38.8(23.8～92.6)pg/mL，均低于aGVHD组[2 791.2(1 698.4～3 468.2)、191.0(113.5～620.2)和77.0(41.5～162.0)pg/mL]，差异均有统计学意义(Z＝－2.926、－4.420和－3.393，P均<0.05)；＋90 d时，无aGVHD组患者sST2水平[78.6(51.0～107.1)pg/mL]低于aGVHD组[146.9(81.0～327.8)pg/mL]，差异有统计学意义(Z＝－3.578，P<0.05)。移植后＋56和＋90 d时，Ⅱ～Ⅳ度aGVHD组患者sTNFR1水平依次为3 245.4(2 804.6～3 557.6)和2 891.2(2 024.6～4 534.0)pg/mL，Reg3α水平依次为162.0(65.4～310.3)和92.5(58.1～157.7)pg/mL，均高于Ⅰ度aGVHD组[sTNFR1依次为2 009.7(1 599.5～3 259.1)和1 870.9(1 620.2～2 334.4)pg/mL、Reg3α依次为53.7(33.2～79.7)和43.9(39.2～64.7)pg/mL]，差异均有统计学意义(Z＝－2.639、－2.242、－3.026和－2.743，P均<0.05)。＋90 d时，Ⅱ～Ⅳ度aGVHD组患者elafin水平[14.0(10.3～24.7)pg/mL]高于Ⅰ度aGVHD组[8.4(7.5～14.3)pg/mL]，差异有统计学意义(Z＝－2.162，P<0.05)。胃肠道aGVHD组患者移植后＋28、＋56和＋90 d Reg3α水平依次为94.7(27.9～307.8)、306.4(162.1～524.4)和124.5(70.1～312.8)pg/mL，非胃肠道aGVHD组依次为33.5(19.6～57.3)、53.8(33.8～81.7)和43.9(37.6～66.7)pg/mL，差异均有统计学意义(Z＝－2.352、－3.857和－2.800，P均<0.05)。＋56和＋90 d时，胃肠道aGVHD组患者sTNFR1水平依次为3 250.5(2 980.8～4 413.2)和4 534.0(2 419.4～6 171.2)pg/mL，非胃肠道aGVHD组依次为2 189.4(1 609.7～3 297.1)和1 885.2(1 715.0～2 530.0)pg/mL，差异均有统计学意义(Z＝－2.842和－2.100，P均<0.05)。

结论

血清生物标志物(sST2、sTNFR1、Reg3α和elafin)水平与allo-HSCT后aGVHD发生及严重程度相关，这些指标可用于辅助临床诊断和干预。

关键词: 生物标志物, 急性移植物抗宿主病, 异基因造血干细胞移植, 细胞因子
Objective

To explore the correlation of IL-6, IL-8, soluble tumor necrosis factor receptor 1 (sTNFR1), regenerating islet-derived protein 3-alpha (Reg3α), soluble suppression of tumorigenesis 2 (sST2) and elafin with acute graft versus host disease (aGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Methods

A retrospective analysis was conducted on the clinical data of 106 patients who underwent allo-HSCT in the Department of Hematology at the 940th Hospital of the Joint Logistics Support Force of PLA between January 2019 and January 2023. Forty-nine patients who developed aGVHD were assigned to the aGVHD group, while 57 patients without aGVHD were included in the non-aGVHD group. Peripheral blood samples were collected from all patients at post-transplantation days + 28, + 56, and + 90 for cytokine quantification. Intergroup comparisons of normally distributed continuous variables were performed using the independent samples t-test. The Mann-Whitney U test was employed for non-normally distributed continuous variables. Categorical variables were compared using the chi-square test. A P-value < 0.05 was considered statistically significant.

Results

At days + 28, sST2 level was significantly lower in the non-aGVHD group [52.2 (34.9-93.0) pg/mL] compared to the aGVHD group [98.2 (58.3-186.7) pg/mL], Z=-3.268, P < 0.05. At days + 56, the non-aGVHD group exhibited significantly reduced level of sTNFR1 [1 971.2 (1 656.8-2 537.0) pg/mL], sST2 [76.4 (40.0-134.4) pg/mL], and Reg3α [38.8 (23.8-92.6) pg/mL] relative to the aGVHD group [sTNFR1 2 791.2 (1 698.4-3 468.2) pg/mL, sST2 191.0 (113.5-620.2) pg/mL, Reg3α 77.0 (41.5-162.0) pg/mL], Z=-2.926, -4.420 and -3.393, all P < 0.05. At days + 90, the sST2 level was lower in the non-aGVHD group [78.6 (51.0-107.1) pg/mL] than the aGVHD group [146.9 (81.0-327.8) pg/mL], Z=-3.578, P<0.05. Patients with grade Ⅱ-Ⅳ aGVHD demonstrated significantly elevated sTNFR1 level at days + 56 [3 245.4 (2 804.6-3 557.6) pg/mL] and days + 90 [2 891.2 (2 024.6-4 534.0) pg/mL], as well as higher Reg3α level at days + 56 [162.0 (65.4-310.3) pg/mL] and days + 90 [92.5 (58.1-157.7) pg/mL] compared to those with grade Ⅰ aGVHD [sTNFR1 2 009.7 (1 599.5-3 259.1) pg/mL at days + 56, 1 870.9 (1 620.2-2 334.4) pg/mL at days + 90, Reg3α 53.7 (33.2-79.7) pg/mL at days + 56, 43.9 (39.2-64.7) pg/mL at days + 90], Z=-2.639, -2.242, -3.026 and -2.743, all P<0.05. Additionally, elafin level was significantly higher in the grade Ⅱ-Ⅳ aGVHD group [14.0 (10.3-24.7) pg/mL] versus the grade Ⅰ group [8.4 (7.5-14.3) pg/mL] at days + 90 (Z=-2.162, P<0.05). Patients in the gastrointestinal aGVHD group exhibited significantly increased Reg3α level at days + 28 [94.7 (27.9-307.8) pg/mL], days + 56 [306.4 (162.1-524.4) pg/mL], and days + 90 [124.5 (70.1-312.8) pg/mL] compared to those in the non-gastrointestinal aGVHD group [33.5 (19.6-57.3), 53.8 (33.8-81.7) and 43.9 (37.6-66.7) pg/mL, respectively], Z= -2.352, -3.857 and -2.800, all P<0.05. Similarly, sTNFR1 level significantly elevated in the gastrointestinal aGVHD group at days + 56 [3 250.5 (2 980.8-4 413.2) pg/mL] and days + 90 [4 534.0 (2 419.4-6 171.2) pg/mL] relative to the non-gastrointestinal aGVHD group [2 189.4 (1 609.7-3 297.1) pg/mL and 1 885.2 (1 715.0-2 530.0) pg/mL, respectively], Z=-2.842 and -2.100, all P<0.05.

Conclusion

The serum biomarkers (sST2, sTNFR1, Reg3α and elafin) are associated with the occurrence and severity of aGVHD in patients treated with allo-HSCT, which may be valuable for clinical diagnosis and intervention.

Key words: Biomaker, Acute graft versus host disease, Allogeneic hematopoietic stem cell transplantation, Cytokine
表1 无aGVHD和aGVHD组患者一般资料比较
临床特征 无aGVHD组(n＝57) aGVHD组(n＝49) t/χ2值 P值
患者年龄(岁，±s) 31.0±10.1 28.9±13.5 0.874 >0.05
供者年龄(岁，±s) 28.0±12.7 32.5±14.0 －1.771 >0.05
原发病[例(%)]     11.924 >0.05
MDS 4( 7.0%) 3( 6.1%)    
HAL 1( 1.8%) 1( 2.1%)    
ALL 15(26.3%) 15(30.6%)    
AA 8(14.0%) 11(22.4%)    
APDS 0 1( 2.1%)    
AML 29(50.9%) 18(36.7%)    
供受者性别关系[例(%)]     8.248 <0.05
男性供者/男性受者 17(29.8%) 26(53.1%)    
男性供者/女性受者 20(35.2%) 14(28.6%)    
女性供者/男性受者 10(17.5%) 7(14.3%)    
女性供者/女性受者 10(17.5%) 2( 4.0%)    
HLA配型[例(%)]     4.793 <0.05
半相合 40(70.2%) 43(87.8%)    
全相合 17(29.8%) 6(12.2%)    
供受者血型(例，相同/不相同) 34/23 32/17 16.049 >0.05
MNC(×108/kg, ±s) 9.64±3.22 9.58±2.69 0.101 >0.05
CD34＋细胞(×106/kg, ±s) 5.29±2.66 5.26±2.30 0.068 >0.05
表2 aGVHD组与无aGVHD组患者移植后血清生物标志物比较结果[pg/mL，M(P25，P75)]
细胞因子 术后时间(d) 无aGVHD组(n＝57) aGVHD组(n＝49) Z值 P值
IL-6 ＋28 10.2 (6.2～24.0) 8.0 (4.3～17.7) －1.473 >0.05
  ＋56 11.0 (5.2～20.7) 6.5 (4.2～14.7) －0.384 >0.05
  ＋90 9.5 (6.6～13.7) 11.3 (6.2～20.1) －0.713 >0.05
IL－8 ＋28 8.6 (1.8～19.2) 10.5 (3.1～28.3) －1.238 >0.05
  ＋56 10.3 (2.1～27.2) 15.8 (8.7～47.6) －1.758 >0.05
  ＋90 11.8 (4.5～28.5) 7.8 (4.2～25.0) －0.353 >0.05
sTNFR1 ＋28 2 377.1 (1 677.6～2 996.3) 1 851.0 (1 542.4～3 259.2) －0.705 >0.05
  ＋56 1 971.2 (1 656.8～2 537.0) 2 791.2 (1 698.4～3 468.2) －2.926 <0.05
  ＋90 1 893.0 (1 607.0～2 327.9) 2 080.6 (1 789.9～3 312.8) －1.497 >0.05
sST2 ＋28 52.2 (34.9～93.0) 98.2 (58.3～186.7) －3.268 <0.05
  ＋56 76.4 (40.0～134.4) 191.0 (113.5～620.2) －4.420 <0.05
  ＋90 78.6 (51.0～107.1) 146.9 (81.0～327.8) －3.578 <0.05
Reg3α ＋28 32.9 (17.6～79.9) 42.9 (20.2～66.1) －0.814 >0.05
  ＋56 38.8 (23.8～92.6) 77.0 (41.5～162.0) －3.393 <0.05
  ＋90 44.2 (27.4～86.5) 59.6 (42.9～92.5) －1.645 >0.05
elafin ＋28 9.3 (5.6～13.9) 9.2 (4.5～15.4) －0.063 >0.05
  ＋56 11.2 (6.8～15.5) 12.6 (7.7～23.3) －1.678 >0.05
  ＋90 12.7 (9.6～16.1) 11.7 (7.9～16.7) －0.559 >0.05
表3 Ⅰ度aGVHD组与Ⅱ～Ⅳ度aGVHD组患者移植后血清生物标志物比较结果[pg/mL，M (P25，P75)]
细胞因子 术后时间(d) Ⅰ度aGVHD组(n＝23) Ⅱ～Ⅳ度aGVHD组(n＝26) Z值 P值
IL-6 ＋28 8.7 (5.1～21.7) 8.0 (3.1～16.9) －0.491 >0.05
  ＋56 7.3 (3.7～14.1) 5.8 (4.7～25.1) －1.820 >0.05
  ＋90 14.9 (4.2～22.0) 9.8 (7.0～19.3) 0.000 >0.05
IL-8 ＋28 11.1 (2.8～32.3) 6.3 (2.5～13.3) －0.473 >0.05
  ＋56 16.9 (8.7～45.2) 13.1 (4.2～59.2) －1.218 >0.05
  ＋90 5.7 (3.9～22.1) 11.4 (5.0～50.5) －1.121 >0.05
sTNFR1 ＋28 1 849.8 (1 533.6～3 168.0) 2 376.4 (1 502.8～3 921.5) －1.503 >0.05
  ＋56 2 009.7 (1 599.5～3 259.1) 3 245.4 (2 804.6～3 557.6) －2.639 <0.05
  ＋90 1 870.9 (1 620.2～2 334.4) 2 891.2 (2 024.6～4 534.0) －2.242 <0.05
sST2 ＋28 103.9 (64.6～439.2) 97.5 (36.6～150.4) －0.180 >0.05
  ＋56 169.0 (101.0～652.6) 213.0 (109.3～554.5) －1.547 >0.05
  ＋90 146.1 (75.8～275.2) 146.9 (86.5～546.5) －0.440 >0.05
Reg3α ＋28 32.8 (19.0～62.1) 53.3 (25.3～94.7) －0.521 >0.05
  ＋56 53.7 (33.2～79.7) 162.0 (65.4～310.3) －3.026 <0.05
  ＋90 43.9 (39.2～64.7) 92.5 (58.1～157.7) －2.743 <0.05
elafin ＋28 7.0 (4.4～17.0) 9.5 (4.8～14.9) －0.711 >0.05
  ＋56 9.1 (7.6～24.0) 14.2 (10.7～30.6) －0.523 >0.05
  ＋90 8.4 (7.5～14.3) 14.0 (10.3～24.7) －2.162 <0.05
表4 胃肠道aGVHD组与非胃肠道aGVHD组患者移植后血清生物标志物比较结果[pg/mL，M(P25，P75)]
细胞因子 术后时间(d) 胃肠道aGVHD组(n＝19) 非胃肠道aGVHD组(n＝30) Z值 P
sTNFR1 ＋28 3 492.0(1 575.3～4 857.6) 1 851.0(1 553.6～2 925.2) －0.773 >0.05
  ＋56 3 250.5(2 980.8～4 413.2) 2 189.4(1 609.7～3 297.1) －2.842 <0.05
  ＋90 4 534.0(2 419.4～6 171.2) 1 885.2(1 715.0～2 530.0) －2.100 <0.05
Reg3α ＋28 94.7( 27.9～307.8) 33.5(19.6～57.3) －2.352 <0.05
  ＋56 306.4(162.1～524.4) 53.8(33.8～81.7) －3.857 <0.05
  ＋90 124.5( 70.1～312.8) 43.9(37.6～66.7) －2.800 <0.05
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