非血缘脐血干细胞移植和同胞外周血干细胞移植免疫重建与慢性移植物抗宿主病的研究

Correlation between immune reconstitution and chronic graft-versus-host disease after unrelated cord blood transplantation and sibling peripheral blood stem cell transplantation

目的探究恶性血液病患者非血缘脐血干细胞移植(UCBT)和同胞外周血干细胞移植(PBSCT)后免疫重建与慢性移植物抗宿主病(cGVHD)的关系。方法以2018年3月至2019年8月在中国科学技术大学附属第一医院行UCBT(96例)和PBSCT(28例)的患者为研究对象。采用流式细胞术检测两组患者移植后第1、3、6、9、12个月外周血免疫细胞,并根据是否发生cGVHD进行分组,探究两种移植类型的免疫细胞重建与cGVHD之间的相关性。结果①UCBT组移植后1年中重度cGVHD累积发生率显著低于PBSCT组[9.38%(95%CI 3.35%~15.02%)对28.57%(95%CI 9.72%~43.50%),P=0.008];UCBT组移植后2年cGVHD、中重度cGVHD累积发生率均低于PBSCT组[15.60%(95%CI 9.20%~23.60%)对32.10%(95%CI 15.80%~49.70%),P=0.047;10.40%(95%CI 5.30%~17.50%)对28.60%(95%CI 13.30%~46.00%),P=0.014]。②UCBT组CD4+T细胞计数在移植后第6、9、12个月均高于PBSCT组[59.00(36.70~89.65)×10^(7)/L对31.40(18.10~44.00)×10^(7)/L,P<0.001;71.30(49.60~101.45)×10^(7)/L对41.60(25.82~56.27)×10^(7)/L,P<0.001;83.00(50.17~121.55)×10^(7)/L对44.85(31.62~62.10)×10^(7)/L,P<0.001],CD4+T细胞比例始终高于PBSCT组(P<0.05)。PBSCT组B细胞计数和比例在移植后第1个月高于UCBT组[0.70(0.30~1.70)×10^(7)/L对0.10(0~0.30)×10^(7)/L,P<0.001;0.45%(0.30%~2.20%)对0.20%(0.10%~0.40%),P=0.002];UCBT组B细胞计数和比例在移植后第9、12个月高于PBSCT组[53.80(28.00~103.20)×10^(7)/L对23.35(5.07~35.00)×10^(7)/L,P<0.001;21.45%(11.80%~30.45%)对9.00%(3.08%~16.73%),P<0.001。66.70(36.97~98.72)×10^(7)/L对20.85(7.72~39.40)×10^(7)/L,P<0.001;22.20%(14.93%~29.68)%对8.75%(5.80%~18.93%),P<0.001]。UCBT组调节性B细胞(Breg)计数和比例在移植后第6、9和12个月高于PBSCT组[1.23(0.38~3.52)×10^(7)/L对0.05(0~0.84)×10^(7)/L,P<0.001;5.35%(1.90%~12.20%)对1.45%(0%~7.78%),P=0.002。2.25(1.07~6.71)×10^(7)/L对0.12(0~0.77)×10^(7)/L,P<0.001;6.25%(2.00%~12.33%)对0.80%(0%~5.25%),P<0.001。3.69(0.83~8.66)×10^(7)/L对0.46(0~0.93)×10^(7)/L,P<0.001;6.15%(1.63%~11.75%)对1.40%(0.18%~5.85%),P<0.001]。③UCBT患者中非cGVHD组的B细胞计数在移植后第6、12个月均高于中重度cGVHD组(P=0.038,P=0.043);非cGVHD组的B细胞比例在移植后第6个月高于中重度cGVHD组(P=0.049)。UCBT患者中非cGVHD组的Breg细胞计数在移植后第6、9、12个月高于中重度cGVHD组(P=0.006,P=0.028,P=0.050);非cGVHD组的Breg细胞比例在移植后第9个月高于中重度cGVHD组(P=0.038)。④PBSCT患者中非cGVHD组的B和Breg细胞绝对数和比例与中重度cGVHD组差异无统计学意义。结论在免疫细胞重建过程中,UCBT组的Breg细胞高于PBSCT组,并且两种移植类型的非cGVHD组的Breg细胞始终较中重度cGVHD组高,表明Breg细胞能够降低cGVHD的发生,揭示了UCBT组cGVHD发生率较低的可能原因。

Objective To explore the relationship between the reconstitution of immune cells in patients with hematological malignancies and the occurrence of chronic graft-versus-host disease(cGVHD)after treatment with unrelated cord blood transplantation(UCBT)and sibling peripheral blood stem cell transplantation(PBSCT).Methods A total of 124 patients undergoing allogenic hematopoietic stem cell transplantation(allo-HSCT)in the First Affiliated Hospital of University of Science and Technology of China from March 2018 to August 2019,including 96 patients with UCBT and 28 patients with PBSCT.Peripheral blood immune cells of patients with UCBT and PBSCT were detected at 1,3,6,9,and 12 months after transplantation using flow cytometry,and both UCBT and PBSCT patients were divided into cGVHD and non-cGVHD groups based on whether cGVHD occurred to explore the correlation between the immune cells reconstitution of the two types of transplantation and cGVHD.Results①The cumulative incidence of the moderate to severe cGVHD in the UCBT group was significantly lower than that in the PBSCT group[9.38%(95%CI 3.35%-15.02%)vs 28.57%(95%CI 9.72%-43.50%),P=0.008];the 2-year cumulative incidence of cGVHD and moderate to severe cGVHD in the UCBT group was lower than that in the PBSCT group[15.60%(95%CI 9.20%-23.60%)vs 32.10%(95%CI 15.80%-49.70%),P=0.047;10.40%(95%CI 5.30%-17.50%)vs 28.60%(95%CI 13.30%-46.00%),P=0.014].②The absolute counts of CD4+T cells in the UCBT group were higher than those in the PBSCT group at 6,9,and 12 months after transplantation[59.00(36.70-89.65)×10^(7)/L vs 31.40(18.10-44.00)×10^(7)/L,P<0.001;71.30(49.60-101.45)×10^(7)/L vs 41.60(25.82-56.27)×10^(7)/L,P<0.001;83.00(50.17-121.55)×10^(7)/L vs 44.85(31.62-62.10)×10^(7)/L,P<0.001];the proportions of CD4+T cells in the UCBT group were always higher than those in the PBSCT group(P<0.05).The absolute counts and proportions of B cells in the PBSCT group were higher than those in the UCBT group at the first month after transplantation[0.70(0.30-1.70)×10^(7)/L vs 0.10(0-0.30)×10^(7)/L,P<0.001;0.45%(0.30%-2.20%)vs 0.20%(0.10%-0.40%),P=0.002];the absolute counts and proportions of B cells in the UCBT group were higher than those in the PBSCT group at 9 and 12 months after transplantation[53.80(28.00-103.20)×10^(7)/L vs 23.35(5.07-35.00)×10^(7)/L,P<0.001;21.45(11.80-30.45)%vs 9.00%(3.08%-16.73%),P<0.001.66.70(36.97-98.72)×10^(7)/L vs 20.85(7.72-39.40)×10^(7)/L,P<0.001;22.20%(14.93%-29.68%)vs 8.75%(5.80%-18.93%),P<0.001].The absolute counts and proportions of regulatory B(Breg)cells in the UCBT group were higher than those in the PBSCT group at 6,9,and 12 months after transplantation[1.23(0.38-3.52)×10^(7)/L vs 0.05(0-0.84)×10^(7)/L,P<0.001;5.35%(1.90%-12.20%)vs 1.45%(0-7.78%),P=0.002.2.25(1.07-6.71)×10^(7)/L vs 0.12(0-0.77)×10^(7)/L,P<0.001;6.25%(2.00%-12.33%)vs 0.80%(0-5.25%),P<0.001.3.69(0.83-8.66)×10^(7)/L vs 0.46(0-0.93)×10^(7)/L,P<0.001;6.15%(1.63%-11.75%)vs 1.40%(0.18%-5.85%),P<0.001].The absolute counts and proportions of CD3+T cells,CD8+T cells,and Treg cells in the UCBT group were not significantly different from those in the PBSCT group.③The absolute counts of B cells in the non-cGVHD group of UCBT patients were higher than those in the moderate to severe cGVHD group at 6 and 12 months after transplantation(P=0.038,P=0.043);the proportions of B cells in the non-cGVHD group were higher than those in the moderate to severe cGVHD group at 6 months after transplantation(P=0.049).The absolute counts of Breg cells in the non-cGVHD group of patients with UCBT were higher than those in the moderate to severe cGVHD group at 6,9,and 12 months after transplantation(P=0.006,P=0.028,P=0.050);the proportions of Breg cells in the non-cGVHD group were higher than those in the moderate to severe cGVHD group at 9 months after transplantation(P=0.038).④The absolute counts and proportions of B and Breg cells in the non-cGVHD group of patients with PBSCT were not statistically different than those in the moderate to severe cGVHD group.Conclusion In the process of immune cell reconstitution,the Breg cells in the UCBT group were higher than those in the PBSCT group,and the Breg cells in the non-cGVHD group of the two types of transplantation were always higher than those in the moderate to severe cGVHD group,indicating that Breg cells can reduce the occurrence of cGVHD,revealing the possible reason for the lower incidence of cGVHD in the UCBT group.