Dynamic changes of lymphocyte subsets and their correlation with renal function in recipients with stable graft status after renal transplantation
-
摘要:
目的 探讨肾移植术后稳定状态受者外周血淋巴细胞亚群的动态变化及其与肾功能的相关性。 方法 筛选行首次肾移植且术后半年内移植肾功能稳定的受者45例, 采用流式细胞术(FCM)检测受者术后15 d及1、3、6个月共计180份外周血样本淋巴细胞亚群比例和绝对值。分析淋巴细胞亚群随术后时间延长的动态变化及其与血清肌酐(Scr)和血尿素氮(BUN)的相关性。 结果 受者术后4个时间点Scr值比较, 差异均无统计学意义(均为P > 0.05)。术后15 d与术后1个月、术后1个月与术后3个月BUN比较, 差异均有统计学意义(P=0.002、P=0.001);术后15 d与术后1个月比较, CD3+CD8+T细胞、CD3+CD4+T细胞、自然杀伤(NK)细胞比例及CD4/CD8比值, 差异均有统计学意义(P=0.009、P=0.004、P < 0.001、P=0.004)。B细胞比例术后15 d与术后1个月比较、术后1个月与术后3个月比较, 差异均有统计学意义(均为P < 0.001)。CD3+T细胞、CD3+CD8+T细胞、CD3+CD4+T细胞和NK细胞绝对值术后15 d与术后1个月比较, 差异均有统计学意义(P=0.001、P=0.002、P=0.003、P < 0.001)。CD3+CD8+T细胞绝对值术后3个月和术后6个月比较, 差异有统计学意义(P=0.015)。B细胞绝对值术后1个月与术后3个月比较, 差异有统计学意义(P=0.001)。淋巴细胞亚群比例和绝对值与Scr均不相关(均为P > 0.05), CD3+CD8+T细胞、NK细胞比例和绝对值与BUN均呈负相关(P < 0.001~0.05), CD3+CD4+T细胞、B细胞比例与BUN均呈正相关(P < 0.001~0.05), CD3+T细胞绝对值与BUN呈负相关(P < 0.05)。 结论 肾移植术后稳定状态受者的淋巴细胞亚群中T细胞和NK细胞术后1个月内升高至稳定状态, B细胞术后3个月内降低至稳定状态, 且淋巴细胞亚群的动态变化与BUN相关。 Abstract:Objective To investigate the dynamic changes of peripheral blood lymphocyte subsets and their correlation with renal function in recipients with stable graft status after renal transplantation. Methods Forty-five recipients who underwent renal transplantation for the first time and had stable graft function within postoperative 6 months were selected. The proportion and absolute value of lymphocyte subsets were detected by flow cytometry (FCM) in 180 peripheral blood samples from recipients at 15 d, 1, 3 and 6 months after renal transplantation. The dynamic changes of lymphocyte subsets with the extension of postoperative time and their correlation with serum creatinine (Scr) and blood urea nitrogen (BUN) were analyzed. Results The Scr levels did not significantly differ at 4 time points after renal transplantation (all P > 0.05). The BUN levels significantly differed between 15 d and 1 month after renal transplantation, and between 1 and 3 months after renal transplantation (P=0.002, P=0.001). The proportion of CD3+CD8+T cells, CD3+CD4+T cells, natural killer (NK) cells and CD4/CD8 ratio at postoperative 15 d significantly differed from those at 1 month after operation (P=0.009, P=0.004, P < 0.001, P=0.004). The proportion of B cells significantly differed between 15 d and 1 month, and between 1 and 3 months after renal transplantation (both P < 0.001). The absolute values of CD3+T cells, CD3+CD8+T cells, CD3+CD4+T cells and NK cells at postoperative 15 d significantly differed from those at 1 month after renal transplantation (P=0.001, P=0.002, P=0.003, P < 0.001). The absolute values of CD3+CD8+T cells significantly differed between 3 and 6 months after operation (P=0.015). The absolute value of B cells at 1 month after renal transplantation significantly differed from that at 3 months after renal transplantation (P=0.001). The proportion and absolute value of lymphocyte subsets were not significantly correlated with the Scr level (both P > 0.05). The proportion and absolute value of CD3+CD8+T cells and NK cells were negatively correlated with BUN (P < 0.001-0.05), whereas the proportion of CD3+CD4+T cells and B cells was positively correlated with the BUN level (P < 0.001-0.05). The absolute value of CD3+T cells was negatively associated with the BUN level (P < 0.05). Conclusions T cells and NK cells in the lymphocyte subsets of stable recipients raise to the stable state within 1 month after renal transplantation, whereas B cells decrease to stable state within 3 months renal transplantation. The dynamic changes of lymphocyte subsets are correlated with the BUN level. -
表 1 肾移植受者不同时间点的淋巴细胞亚群比例和CD4/CD8比值
Table 1. The proportion of lymphocyte subsets and CD4/CD8 ratio in renal transplant recipients at different time points(x±s)
术后时间 n CD3+T细胞(%) CD3+CD8+ T细胞(%) CD3+CD4+ T细胞(%) CD4/CD8 NK细胞(%) B细胞(%) 15 d 45 75±8 27±9 46±10 2.0±1.1 7±5 16±7 1个月 45 76±9 31±11a 43±11a 1.6±1.0a 12±7b 10±6b 3个月 45 77±9 32±9 43±11 1.5±0.8 13±8 8±4c 6个月 45 79±9 33±10 42±10 1.4±0.7 14±8 7±4 注:术后15 d与术后1个月比较, aP < 0.01、bP < 0.001;术后1个月与术后3个月比较, cP < 0.001。 表 2 肾移植受者不同时间点的淋巴细胞亚群绝对值
Table 2. Absolute value of lymphocyte subsets in renal transplant recipients at different time points (x±s, ×106/L)
术后时间 n CD3+T细胞 CD3+CD8+T细胞 CD3+CD4+T细胞 NK细胞 B细胞 15 d 45 1 243±665 452±277 752±432 100±74 258±173 1个月 45 1 729±1 005b 744±634a 945±523a 248±179b 233±173 3个月 45 1 699±772 723±464 932±422 298±240 166±107c 6个月 45 1 910±819 836±469d 1 003±466 328±251 165±108 注:术后15 d与术后1个月比较, aP < 0.01、bP < 0.001;术后1个月与术后3个月比较, cP < 0.001;术后3个月与术后6个月比较, dP < 0.05/3。 表 3 肾移植受者淋巴细胞亚群与BUN的相关性
Table 3. Correlation between lymphocyte subsets and BUN in renal transplant recipients
指标 比例 绝对值 r P值 r P值 CD3+T细胞与BUN -0.071 > 0.05 -0.169 < 0.05 CD3+CD8+T细胞与BUN -0.175 < 0.05 -0.202 < 0.01 CD3+CD4+T细胞与BUN 0.151 < 0.05 -0.090 > 0.05 NK细胞与BUN -0.322 < 0.001 -0.316 < 0.001 B细胞与BUN 0.423 < 0.001 0.094 > 0.05 -
[1] MENDOZA ROJAS A, HESSELINK DA, VAN BESOUW NM, et al. Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of de novo anti-HLA donor-specific antibodies in kidney transplant recipients[J]. Expert Rev Clin Immunol, 2019, 15(12):1323-1331. DOI: 10.1080/1744666X.2020.1693263. [2] PETRARA MR, SERRAINO D, DI BELLA C, et al. Immune activation, immune senescence and levels of Epstein Barr virus in kidney transplant patients: impact of mTOR inhibitors[J]. Cancer Lett, 2020, 469:323-331. DOI: 10.1016/j.canlet.2019.10.045. [3] FLABOURIS K, CHADBAN S, LADHANI M, et al. Body mass index, weight-adjusted immunosuppression and the risk of acute rejection and infection after kidney transplantation: a cohort study[J]. Nephrol Dial Transplant, 2019, 34(12):2132-2143. DOI: 10.1093/ndt/gfz095. [4] 范宇, 石炳毅, 钱叶勇, 等.肾移植术后BK病毒感染对移植肾功能影响的临床研究[J].器官移植, 2018, 9(1):51-57. DOI: 10.3969/j.issn.1674-7445.2018.01.007.FAN Y, SHI BY, QIAN YY, et al. Clinical study on the effect of BK virus infection on renal allograft function after renal transplantation[J]. Organ Transplant, 2018, 9(1):51-57. DOI: 10.3969/j.issn.1674-7445.2018.01.007. [5] 范宇.肾移植术后BK病毒感染流行病学监测及病毒特异性细胞免疫反应的研究[D].北京: 中国人民解放军医学院, 2014. [6] SIEŃKO J, KOTOWSKI M, PACZKOWSKA E, et al. Correlation between stem and progenitor cells number and immune response in patients after allogeneic kidney transplant[J]. Ann Transplant, 2018, 23:874-878. DOI: 10.12659/AOT.912686. [7] ALOUFI M, ALZAHRANY G, ABDULMAJEED N, et al. Viral infections after kidney transplantation in a cohort of children: a retrospective single-center study[J]. Transplant Proc, 2019, 51(2):522-525. DOI: 10.1016/j.transproceed.2019.01.010. [8] WRIGHT S, KLEVEN D, KAPOOR R, et al. Recurring norovirus & sapovirus infection in a renal transplant patient[J]. IDCases, 2020, 20:e00776. DOI: 10.1016/j.idcr.2020.e00776. [9] ERGIN G, DEĞER SM, KÖPRÜ B, et al. High neutrophil-to-lymphocyte ratio predicts acute allograft rejection in kidney transplantation: a retrospective study[J]. Turk J Med Sci, 2019, 19(2):525-530. DOI: 10.3906/sag-1811-41. [10] ZHANG H, ZHENG C, LI X, et al. Diagnostic performance of donor-derived plasma cell-free DNA fraction for antibody-mediated rejection in post renal transplant recipients: a prospective observational study[J]. Front Immunol, 2020, 11:342. DOI: 10.3389/fimmu.2020.00342. [11] ESTEBAN DE LA ROSA RJ, BRAVO SOTO JA, LUNA DEL CASTILLO JD, et al. Influence of age, sex, and hepatitis C virus infection on peripheral blood lymphocyte subsets in stable kidney transplantation[J]. Transplant Proc, 2003, 35(8):2905-2907. DOI: 10.1016/j.transproceed.2003.10.069. [12] 王晓勃.T淋巴细胞亚群检测应用于肾移植术后排斥反应与巨细胞病毒感染鉴别中的价值分析[J].临床研究, 2018, 26(10):128-129. DOI: 10.3969/j.issn.1004-8650.2018.10.073.WANG XB. The value analysis of T lymphocyte subgroup detection in the differentiation of rejection and cytomegalovirus infection after renal transplantation[J]. Clin Res, 2018, 26(10):128-129. DOI: 10.3969/j.issn.1004-8650.2018.10.073. [13] 尚文俊, 杨先雷, 王志刚, 等.淋巴细胞亚群与肾移植术后感染及排斥反应的关系[J].中华器官移植杂志, 2017, 38(6):353-358.DOI: 10.3760/cma.j.issn.0254-1785.2017.06.007.SHANG WJ, YANG XL, WANG ZG, et al. Relationship between lymphocyte subsets with infection and rejection after renal transplantation[J]. Chin J Organ Transplant, 2017, 38(6):353-358. DOI: 10.3760/cma.j.issn.0254-1785.2017.06.007. [14] 李详立, 王爱萍.监测T淋巴细胞亚群在评估肾移植术后免疫状态的临床意义[J].医药前沿, 2015, 5(33):168-169. DOI: 10.3969/j.issn.2095-1752.2015.33.149.LI XL, WANG AP. Clinical significance of monitoring T lymphocyte subsets in evaluating immune status after renal transplantation[J]. J Front Med, 2015, 5(33):168-169. DOI: 10.3969/j.issn.2095-1752.2015.33.149. [15] 魏丽, 刁宏燕, 吴炜, 等.肾移植术后T淋巴细胞亚群和NK细胞百分比参考范围的研究[J].检验医学与临床, 2015, 12(2):155-156. DOI: 10.3969/j.issn.1672-9455.2015.02.006.WEI L, DIAO HY, WU W, et al. Study on reference values of T-lymphocyte subsets and NK cell percentage after renal transplant operation[J]. Lab Med Clin, 2015, 12(2):155-156. DOI: 10.3969/j.issn.1672-9455.2015.02.006. [16] MACHADO FP, VICARI AR, SPULDARO F, et al. Polyclonal anti T-lymphocyte antibody therapy monitoring in kidney transplant recipients: comparison of CD3+ T cell and total lymphocyte counts[J]. Einstein (Sao Paulo), 2018, 16(4):eAO4278. DOI: 10.31744/einstein_journal/2018AO4278. [17] 李国文.监测T淋巴细胞亚群在评估肾移植术后免疫状态的临床意义[D].广州: 南方医科大学, 2014. [18] VACHER-COPONAT H, BRUNET C, MOAL V, et al. Tacrolimus/mycophenolate mofetil improved natural killer lymphocyte reconstitution one year after kidney transplant by reference to cyclosporine/azathioprine[J]. Transplantation, 2006, 82(4):558-566. DOI: 10.1097/01.tp.0000229390.01369.4a. [19] BARNES PJ. Role of HDAC2 in the pathophysiology of COPD[J]. Annu Rev Physiol, 2009, 71:451-464. DOI: 10.1146/annurev.physiol.010908.163257. [20] HOWELL J, SAWHNEY R, TESTRO A, et al. Cyclosporine and tacrolimus have inhibitory effects on Toll-like receptor signaling after liver transplantation[J]. Liver Transpl, 2013, 19(10):1099-1107. DOI: 10.1002/lt.23712. [21] YAZDANI S, CALLEMEYN J, GAZUT S, et al. Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation[J]. Kidney Int, 2019, 95(1):188-198. DOI: 10.1016/j.kint.2018.08.027. [22] 王旭珍, 薛武军, 田普训, 等.他克莫司对肾移植受者外周血NK和NKT细胞比例的影响及临床意义[J].细胞与分子免疫学杂志, 2013, 29(5):533-534, 537. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=xbyfzmyxzz201305025WANG XZ, XUE WJ, TIAN PX, et al. The effect and clinical significance of tacrolimus on peripheral blood NK and NKT cells in kidney transplant recipients[J]. Chin J Cell Mol Immunol, 2013, 29(5):533-534, 537. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=xbyfzmyxzz201305025 [23] 党受涛. T淋巴细胞亚群在肾移植术后长期存活患者中的临床意义[D].北京: 首都医科大学, 2011. [24] SICARD A, CHEN CC, MORELON E, et al. Alloimmune-induced intragraft lymphoid neogenesis promotes B-cell tolerance breakdown that accelerates chronic rejection[J]. Curr Opin Organ Transplant, 2016, 21(4):368-374. DOI: 10.1097/MOT.0000000000000329. [25] CHRISTAKOUDI S, RUNGLALL M, MOBILLO P, et al. Steroid regulation: an overlooked aspect of tolerance and chronic rejection in kidney transplantation[J]. Mol Cell Endocrinol, 2018, 473:205-216. DOI: 10.1016/j.mce.2018.01.021.