PD-1在急性白血病异基因造血干细胞移植后T淋巴细胞的表达

doi:10.3969/j.issn.1004-583X.2021.03.013

摘要/Abstract

摘要：

目的探究PD-1在急性白血病患者异基因造血干细胞移植(allo-HSCT)后外周血T淋巴细胞表达的动态变化及临床意义。方法采集23例健康志愿者(对照组),40例急性白血病患者allo-HSCT(移植组)后1、2、3、4.5、6个月的外周血标本,采用流式细胞术对各标本CD3⁺CD4⁺、CD3⁺CD8⁺ T淋巴细胞程序性死亡蛋白1(PD-1)的表达水平进行监测,分析移植组和对照组的PD-1表达水平差异。结果急性白血病患者allo-HSCT后1、2个月PD-1在CD3⁺CD4⁺、CD3⁺CD8⁺T淋巴细胞的表达水平高于对照组;3、4.5、6个月PD-1在CD3⁺CD4⁺ T细胞的表达水平高于对照组, 且随移植时间呈现下降趋势,在CD3⁺CD8⁺ T淋巴细胞的表达水平与对照组差异无明显统计学意义(P均>0.05)。结论急性白血病患者allo-HSCT后早期PD-1在CD3⁺CD4⁺ T淋巴细胞的表达较正常水平升高且随移植时间呈现下降趋势;在CD3⁺CD8⁺ T淋巴细胞的表达于移植后早期呈现一过性升高。

关键词: 白血病, 程序性细胞死亡受体1, 造血干细胞移植, 淋巴细胞

Abstract:

Objective To explore the dynamic change and clinical significance of PD-1 (programmed cell death protein 1) expression on T-lymphocytes in acute leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods Twenty-three healthy volunteers (the control group) and 40 patients with acute leukemia (the transplantation group) were selected, peripheral blood samples were collected 1, 2, 3, 4, 5, 6 months after allo-HSCT, and PD-1 expression levels on CD3⁺CD4⁺ and CD3⁺CD8⁺ T-lymphocytes were tested by the flow cytometry. The differences of PD-1 expression levels between the allo-HSCT group and the control group were analyzed. Results The expression levels of PD-1 on CD3⁺CD4⁺ and CD3⁺CD8⁺ T-lymphocytes in acute leukemia patients in the transplantation group at 1 and 2 months after allo-HSCT were higher than those of the control group. The PD-1 expression levels on CD3⁺CD4⁺ T-lymphocyte in the transplantation group were higher than those of the control group at 3, 4, 5 and 6 month after allo-HSCT, but they showed a downtrend with the transplantation time, while the PD-1 expression levels in CD3⁺CD8⁺ T-lymphocyte had no obvious statistical significance (P>0.05 for all). Conclusion The PD-1expression levels on CD3⁺CD4⁺ T-lymphocyte in patients with acute leukemia after allo-HSCT were higher than those normal levels at the early stage and showed a downtrend with the transplantation time; while the PD-1 expression levels on CD3⁺CD8⁺ T-lymphocyte were increased transiently at the early stage after allo-HSCT.

Key words: leukemia, programmed cell death protein 1, hematopoietic stem cell transplantation, lymphocyte

中图分类号:

R733.7

刘建宁, 孙立, 牛志云, 温树鹏, 王颖, 张学军, 王福旭. PD-1在急性白血病异基因造血干细胞移植后T淋巴细胞的表达[J]. 临床荟萃, 2021, 36(3): 251-255.

Liu Jianning, Sun Li, Niu Zhiyun, Wen Shupeng, Wang Ying, Zhang Xuejun, Wang Fuxu. Expression of PD-1 on T-lymphocytes in acute leukemia after allogeneic hematopoietic stem cell transplantation[J]. Clinical Focus, 2021, 36(3): 251-255.

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链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2021.03.013

https://huicui.hebmu.edu.cn/CN/Y2021/V36/I3/251

图/表 3

参考文献 22

[1]	Frassoni F, Barrett AJ, Granena A, et al. Relapse after allogeneic bone marrow transplantation for acute leukaemia: a survey by the E.B. M.T. of 117 cases[J]. Br J Haematol, 1988,70(3):317-320. doi: 10.1111/j.1365-2141.1988.tb02488.x URL
[2]	Mielcarek M, Storer BE, Flowers ME, et al. Outcomes among patients with recurrent high-risk hematologic malignancies after allogeneic hematopoietic cell transplantation[J]. Biol Blood Marrow Transplant, 2007,13(10):1160-1168. doi: 10.1016/j.bbmt.2007.06.007 URL
[3]	Fathi AT, Chen YB. Treatment of relapse of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation[J]. Curr Hematol Malig Rep, 2014,9(2):186-192. doi: 10.1007/s11899-014-0209-2 pmid: 24643311
[4]	张之南, 沈悌. 《血液病诊断及疗效标准》[M].3版. 北京: 科学出版社, 2007.
[5]	中华医学会血液学分会. 成人急性髓系白血病(非急性早幼粒细胞白血病)中国诊疗指南(2017年版)[J]. 中华血液学杂志, 2017,38(3):177-182.
[6]	中国抗癌协会血液肿瘤专业委员会. 中国成人急性淋巴细胞白血病诊断与治疗指南(2016年版)[J]. 中华血液学杂志, 2016,37(10):837-845.
[7]	宁红梅, 冯凯, 陈虎, 等. 粘附分子与移植物抗宿主病[J]. 国外医学.输血及血液学分册, 2004,27(2):102-106.
[8]	Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy[J]. Net Rev Immunol, 2012,12(6):443-458.
[9]	Vigorito AC, Campregher PV, Storer BE, et al. Evaluation of NIH consensus criteria for classification of late acute and chronic GVHD[J]. Blood, 2009,114(3):702-708. doi: 10.1182/blood-2009-03-208983 pmid: 19470693
[10]	中华医学会血液学分会干细胞应用学组. 中国异基因造血干细胞移植治疗血液系统疾病专家共识(I)—适应症、预处理方案及供者选择(2014年版)[J]. 中华血液学杂志, 2014,35(8):775-780.
[11]	Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading[J]. Bone Marrow Transplant, 1995,15(6):825-828.
[12]	Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I.Diagnosis and staging working group report[J]. Biol Blood Marrow Transplant, 2005,11(12):945-956. doi: 10.1016/j.bbmt.2005.09.004 URL
[13]	中华医学会血液学分会干细胞应用学组. 中国异基因造血干细胞移植治疗血液系统疾病专家共识(III)—急性移植物抗宿主病(2020年版)[J]. 中华血液学杂志, 2020,41(7):529-536.
[14]	Gianchecchi E, Delfino DV, Fierabracci A. Recent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and autoimmunity[J]. Autoimmun Rev, 2013,12(11):1091-1100. doi: 10.1016/j.autrev.2013.05.003 pmid: 23792703
[15]	孙建军, 冯辉. CD8⁺T细胞耗竭及靶向CD8⁺T细胞免疫治疗的研究进展[J]. 免疫学杂志, 2016,32(9):816-820.
[16]	Simonetta F, Pradier A, Bosshard C, et al. Dynamics of expression of Programmed Cell Death Protein-1 (PD-1) on T cells after allogeneic hematopoietic stem cell transplantation[J]. Front Immunol, 2019,10:1034. doi: 10.3389/fimmu.2019.01034 pmid: 31156625
[17]	Kong Y, Zhang J, Claxton DF, et al. PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation[J]. Blood Cancer J, 2015,5(7):e330. doi: 10.1038/bcj.2015.58 URL
[18]	Noviello M, Manfredi F, Ruggiero E, et al. Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT[J]. Nat Commun, 2019,10(1):1065. doi: 10.1038/s41467-019-08871-1 URL
[19]	Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies[J]. Clin Cancer Res, 2008,14(10):3044-3051. doi: 10.1158/1078-0432.CCR-07-4079 URL
[20]	Ravandi F, Assi R, Daver N, et al. Idarubicin, cytarabine, and nivolumab in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a single-arm, phase 2 study[J]. Lancet Haematol, 2019,6(9):e480-e488. doi: 10.1016/S2352-3026(19)30114-0 pmid: WOS:000483400400011
[21]	Haverkos BM, Abbott D, Hamadani M, et al. PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD[J]. Blood, 2017,130(2):221-228. doi: 10.1182/blood-2017-01-761346 pmid: 28468799
[22]	Bashey A, Medina B, Corringham S, et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation[J]. Blood, 2009,113(7):1581-1588. doi: 10.1182/blood-2008-07-168468 pmid: 18974373

预处理方案	例数	药物	剂量	时间(d)
mBu/Cy	5	Ara-c	2 g/m²	-9
		Bu	3.2 mg/(kg·d)	-8~-6
		Cy	1.8 g/(m²·d)	-5~-4
		MeCCNU	250 mg/m²	-3
mBu/Cy+ATG	17	Ara-c	4 g/(m²·d)	-10~-9
		Bu	3.2 mg/(kg·d)	-8~-6
		Cy	1.8 g/(m²·d)	-5~-4
		ATG	2.5 mg/(kg·d)	-5~-2
Bu/Cy+FLAG	1	Ara-c	4 g/(m²·d)	-10~-9
		Bu	3.2 mg/(kg·d)	-8~-6
		Cy	40 mg/(kg·d)	-5~-4
		Flu	30 mg/(m²·d)	-6~-2
		G-CSF	5 μg/kg
BU/Cy+FLAG+ATG	3	Ara-c	4 g/(m²·d)	-10~-9
		Bu	3.2 mg/(kg·d)	-8~-6
		Cy	40 mg/(kg·d)	-5~-4
		Flu	30 mg/(m²·d)	-6~-2
		G- CSF	5 μg/kg
		ATG	2.5 mg/(kg·d)	-5~-2
TBI/Cy	4	TBI	4 Gy/d	-5~-4
		Cy	60 mg/(kg·d)	-3~-2
TBI/Cy+ATG	7(其中3例加依托泊苷处理)	Cy	1.8 g/(m²·d)	-5~-4
		ATG	2.5 mg/(kg·d)	-5~-2
		TBI	4 Gy/d	-2~-1
TBI/Cy+FLAG+ATG	3	Ara-c	2 g/(m²·d)	-7~-4
		TBI	4 Gy/d	-9~-8
		Cy	40 mg/(kg·d)	-3~-2
		Flu	30 mg/(m²·d)	-7~-4
		ATG	2.5 mg/(kg·d)	-5~-2
		G-CSF	5 μg/kg	-7~-4

预处理方案	例数	药物	剂量	时间(d)
mBu/Cy	5	Ara-c	2 g/m²	-9
		Bu	3.2 mg/(kg·d)	-8~-6
		Cy	1.8 g/(m²·d)	-5~-4
		MeCCNU	250 mg/m²	-3
mBu/Cy+ATG	17	Ara-c	4 g/(m²·d)	-10~-9
		Bu	3.2 mg/(kg·d)	-8~-6
		Cy	1.8 g/(m²·d)	-5~-4
		ATG	2.5 mg/(kg·d)	-5~-2
Bu/Cy+FLAG	1	Ara-c	4 g/(m²·d)	-10~-9
		Bu	3.2 mg/(kg·d)	-8~-6
		Cy	40 mg/(kg·d)	-5~-4
		Flu	30 mg/(m²·d)	-6~-2
		G-CSF	5 μg/kg
BU/Cy+FLAG+ATG	3	Ara-c	4 g/(m²·d)	-10~-9
		Bu	3.2 mg/(kg·d)	-8~-6
		Cy	40 mg/(kg·d)	-5~-4
		Flu	30 mg/(m²·d)	-6~-2
		G- CSF	5 μg/kg
		ATG	2.5 mg/(kg·d)	-5~-2
TBI/Cy	4	TBI	4 Gy/d	-5~-4
		Cy	60 mg/(kg·d)	-3~-2
TBI/Cy+ATG	7(其中3例加依托泊苷处理)	Cy	1.8 g/(m²·d)	-5~-4
		ATG	2.5 mg/(kg·d)	-5~-2
		TBI	4 Gy/d	-2~-1
TBI/Cy+FLAG+ATG	3	Ara-c	2 g/(m²·d)	-7~-4
		TBI	4 Gy/d	-9~-8
		Cy	40 mg/(kg·d)	-3~-2
		Flu	30 mg/(m²·d)	-7~-4
		ATG	2.5 mg/(kg·d)	-5~-2
		G-CSF	5 μg/kg	-7~-4

时间	PD-1/CD3⁺CD4⁺ T	PD-1/CD3⁺CD8⁺ T
移植后1个月	49.39±22.97	38.27±21.12
移植后2个月	43.75±26.75	28.51±20.69
移植后3个月	26.92±22.25	18.79±19.70
移植后4.5个月	28.59±19.83	17.12±18.83
移植后6个月	25.26±16.12	11.64±16.67
F值	5.082	8.492
P值	0.002	0.002

时间	PD-1/CD3⁺CD4⁺ T	PD-1/CD3⁺CD8⁺ T
移植后1个月	49.39±22.97	38.27±21.12
移植后2个月	43.75±26.75	28.51±20.69
移植后3个月	26.92±22.25	18.79±19.70
移植后4.5个月	28.59±19.83	17.12±18.83
移植后6个月	25.26±16.12	11.64±16.67
F值	5.082	8.492
P值	0.002	0.002