HLA配型、群体反应性抗体与肾移植术后早期急性排斥反应的关系

目的：研究人类白细胞抗原(HLA)配型、群体反应性抗体(PRA)与肾移植术后早期急性排斥反应的关系。方法：应用单克隆抗体板、微量序列特异性引物、混合抗原板进行供受者HLA-I类抗原分型、HLA-Ⅱ类基因分型、PRA检测。结果：PRA为低、中、高三组受者的早期急性排斥反应发生率分别为16％、27％、66．6％。HLA位点错配数(MM)为0-1组明显比5—6组早期急性排斥反应率低。结论：良好的组织配型、低水平的PRA，可降低早期急性排斥反应的发生。     

肾移植群体反应性抗体的检测及其临床应用

目的 :探讨人类白细胞抗原 (HLA)群体反应性抗体 (PRA)对肾移植效果的影响。方法 :采用酶联免疫吸附法 (ELISA)对 2 0 6例肾移植受者的血清PRA进行检测。同时对 14 0份血清分成四组包括首次移植术前及术后 1个月 ,半年至 1年肾功能稳定期病人 ,第一次尸肾移植失功恢复血透病人进行PRA检测。结果 :PRA阴性组受者移植术后排斥发生率为 11 85 % ,阳性组受者平均PRA高达 4 6 5 % ,两组比较差异显著 (P <0 0 0 1)。首次移植术前A组PRA阳性率 17 1% ,术后B组PRA阳性率 31 4 % ,肾功能稳定组 (C组 )PRA阳性率 14 3%。而移植失功恢复血透者 (D组 )PRA阳性率达 77 1%。结论 :PRA的检测是肾脏移植术前筛选致敏受者的重要指标 ,对肾脏移植后排斥反应和移植物存活率关系密切。     

抗人类白细胞抗原抗体与抗内皮细胞抗体在肾移植慢性排斥反应中作用的相关性

目的 选择发生慢性排斥反应的肾移植患者,根据人类白细胞抗原(human leukocyte anti-gen,HLA)抗体阳性或抗内皮细胞抗体阳性以及两抗体同时阳性进行分组,并同时检测各组患者的血清中肌酐含量作为判断肾功能的指标.探讨在肾移植慢性排斥反应中抗内皮细胞抗体与抗HLA抗体作用的相关性.方法 抗内皮细胞抗体的检测方法用免疫荧光法,抗HLA抗体应用酶联免疫吸附试验(enzyme linked immunosorbent assay,ELISA),肌酐检测应用的是生化分析仪.结果 移植后处于慢性排斥期抗HLA抗体阳性的患者血清肌酐含量均值为(116.3±5.6)μmol/L,抗内皮细胞抗体阳性的患者血清肌酐含量均值为(114.6±4.7)μmol/L;抗HLA抗体与抗内皮细胞抗体同时阳性的血清标本肌酐含量的中位数是131.2μmol/L,四分位间距为13.6μmol/L;两组间肌酐含量差异有统计学意义(P=0.000).结论 抗内皮细胞抗体和抗HLA抗体均可影响肾移植慢性排斥反应期的肾功能;抗内皮细胞抗体与抗HLA抗体在肾移植慢性排斥期间同时产生,肾功能损害加重.     

再次免疫应答导致肾移植后早期严重急性体液排斥反应

背景：国内外有关预防高致敏受者肾移植后发生超急性、急性排斥反应提高人肾存活率取得满意效果,然而临床对群体反应性抗体检测阴性既往致敏受者肾移植后发生再次免疫应答研究则罕见报道。 目的：探讨群体反应性抗体阴性的既往致敏受者肾移植后早期发生严重急性体液性排斥反应机制,为其早期诊断和治疗既提供参考依据。 方法：选择21例群体反应性抗体阴性术后早期发生严重急性体液性排斥的首次肾移植患者,动态分析移植后14 d内反映急性体液性排斥的相关指标,包括IgG型抗HLA抗体,病理苏木精-伊红染色、C4d及细胞表面分子原位检测。 结果与结论：21例患者既往均有输血或妊娠史;18例患者移植后第7天抗HLAⅠ类IgG抗体阳性率>80%,11例于移植后第7天抗HLA Ⅱ类IgG抗体> 80%;5例女性患者于移植后第5~8天发生移植肾破裂,抗HLAⅠ类和Ⅱ类IgG抗体均>96%;21例受者均检出抗供者特异性抗体(DSA),13例(61.90%)供、受者存在HLA-A2和HLA-A11的错配并产生对应DSA,包括5例移植肾破裂受者;病理组织形态学均有不同程度急性损伤,免疫组化可见管周毛细血管区(PTC)C4d沉积,原位染色CD34(+)、CD68(+)、CD4(+)。提示移植前群体反应性抗体监测不能完全反映受者的预致敏状态;移植后早期监测群体反应性抗体可预测和诊断既往致敏受者急性体液性排斥的发生;C4d、CD68(+)作为其的辅助诊断指标,可提高诊出率;HLA-A2和HLA-A11在既往致敏受者是高危致敏基因。     

延迟性异种移植排斥反应

延迟性异种移植排斥反应是目前异种移植物存活的主要障碍,对ＤＸＲ发病机理的认识和进一步研究,有望发掘新的抑制治疗措施。     

利妥昔单抗在肾移植后抗体介导排斥反应中的作用

背景：国外研究表明,利妥昔单抗在肾移植后抗体介导的排斥反应中具有良好的安全性及有效性,但中国尚缺乏此类研究及报道。 目的：探讨利妥昔单抗在肾移植后抗体介导的排斥反应中的安全性和有效性。 方法：将肾移植后病理诊断为抗体介导的排斥反应的患者18例分为2组,均进行免疫抑制治疗,药物组8例采用单剂利妥昔单抗治疗;对照组10例不使用利妥昔单抗治疗。 结果与结论：用药后6,12个月,药物组肌酐水平均低于同期对照组(P < 0.05)。用药后随访6-12个月,药物组1例患者出现巨细胞病毒血症,1例患者出现泌尿系感染,随访期间无威胁生命的感染发生,人/肾存活率为100%。结果证实,利妥昔单抗在治疗肾移植移植后抗体介导的排斥反应中安全有效。     

移植肾穿刺病理组织中抗体介导的排斥反应

背景：体液性排斥以激素耐受和难治性为其显著的特点,常常发生在免疫高敏的受者身上。 目的：对肾功能不全移植肾进行常规穿刺病理活检,根据病理诊断观察抗体介导性排斥反应的治疗效果,分析移植肾穿刺病理活检的安全性。 方法：选取肾移植后有移植肾穿刺活检指征的患者84例,在B超引导下应用BARD(美国)活检穿刺针行移植肾穿刺活检,活检组织行常规苏木精-伊红染色,组织化学染色,同时常规行C4d免疫组织化学染色,依据Banff’05标准进行病理分型,根据病理状态明确诊断进行相应的临床治疗,观察治疗效果。 结果与结论：84例患者除1例由于组织少难以诊断,其余病理诊断移植肾超急性排斥反应1例,急性抗体介导性排斥反应5例,慢性抗体介导性排斥反应2例,C4d免疫组织化学染色阳性16例。经过治疗8例抗体介导性排斥反应患者中4例移植肾功能得以恢复,3例未恢复,1例移植肾失功,移植肾切除。患者无不良反应发生。结果表明移植肾穿刺病理活检对移植肾无不良影响。     

延迟性异种移植排斥反应

延迟性异种移植排斥反应（ＤＸＲ）是目前异种移植物存活的主要障碍,对ＤＸＲ发病机理的认识和进一步研究,有望发掘新的抑制治疗措施     

抗CD3单克隆抗体在预防肾移植术后急性排斥反应中的作用

目的 :观察抗CD3单克隆抗体在预防肾移植术后急性排斥反应的作用。方法 :16 4例肾移植患者分为两组 ,4 2例移植术后应用抗CD3单克隆抗体 (5mg d)为治疗组 ;其它 12 2例为对照组。观察移植术后人 肾存活率、急性排斥反应及CMV感染的发生率。结果 :治疗组 1年、2年及 3年人存活率与对照组无显著差异 ,而治疗组移植肾存活率明显高于对照组(P <0 0 5 )。治疗组急性排斥反应发生率 (18 6 % )比对照组 (2 8 7% )低 ,P <0 0 5 ,且首次急性排斥反应发生时间明显延长 ,对MP冲击治疗效果好。治疗组CMV感染的发生率 (33 3% )高于对照组 ,P <0 0 5。结论 :肾移植术后预防性使用抗CD3单克隆抗体对提高移植肾存活率 ,降低急性排斥反应发生率有较好的作用 ;用药期间应注意预防及治疗CMV感染。     

肾移植后急性排斥反应的免疫学监测研究进展

当前肾移植发展十分迅速，但移植后的急性排斥反应，仍然是影响长期存活的重要因素。如何通过非侵入性方法尽早发现急性排斥反应，是人们研究的热点之一。本文就肾移植后急性排斥反应早期免疫学检测指标的研究进展进行综述。     

抗CD25单克隆抗体预防肾移植术后急性排异反应的研究

目的 :研究抗CD2 5单克隆抗体预防肾移植术后急性排异反应的作用。方法 :71例肾移植患者随机分为抗CD2 5单克隆抗体治疗组 2 6例与对照组 4 5例 ,治疗组于肾移植手术前后应用抗CD2 5单克隆抗体 2次 ,对术后急性排异反应发生率、移植肾功能及外周血T细胞亚群进行动态监测。结果 :术后 1、3、6、12个月时急性排异反应的发生率治疗组为 7.7%、19 .2 %、2 3.1%、30 .8% ,对照组为 15 .6 %、2 8.9%、35 .6 %、4 6 .7% ,两组比较有显著性差异 (P <0 .0 5 ) ;术后 1、6及 12个月时治疗组移植肾功能优于对照组 (P <0 .0 5 ) ;术后两组CD3+ 与CD4 + 的表达均下降 ,但两组间无显著差异 (P >0 .0 5 )。结论 :抗CD2 5单克隆抗体可以明显降低肾移植术后急性排异反应的发生率 ,而对T细胞亚群无明显影响。     

Significant association between chronic antibody-mediated rejection and donor-specific antibodies against HLA-DRB rather than DQB in renal transplantation

De novo production of antidonor HLA antibody has been reported to be associated with chronic antibody-mediated rejection (CAMR). However, some donor-specific antibodies (DSA) do not seem to cause graft injury. Identification of the DSA responsible for CAMR and establishment of effective screening method for early detection of CAMR are therefore essential. All sera from 586 maintenance renal transplant recipients were examined for HLA antibody using ELISA and Luminex-based assay. Positive sera were divided into high (>20% of positive control), moderate (10-20%), and low (2-10%). Donor specificities were analyzed using single antigen beads. ELISA detected only about half of high HLA antibodies (class I: n = 19, class II: n = 46) measured by Luminex-based assay. DSA against class I and class II were identified in 42% and 87% of high antibodies, respectively, including 78% against DQB and 44% against DRB. Renal dysfunction due to CAMR was closely related to high/moderate DRB DSA (n = 11), but not low DRB DSA (n = 9) nor high/moderate/low DQB DSA alone (n = 20). It was speculated that DRB DSA would be more detrimental to the graft, while DQB DSA were readily detectable in blood circulation. Further study, including detailed pathologic analysis of graft biopsy and long-term follow-up, is necessary.     

整合素与肾脏移植排斥

整合素是一类广泛存在于细胞表面的粘附分子,介导细胞—细胞及细胞—细胞外基质间的粘附及信息传导。近年来研究发现其参与同种移植排斥反应,并与其它粘附分子相互作用,在急性排斥反应中发挥重要作用。以下就该类分子的结构与分类、活化方式、与移植排斥反应关系作一综述。     

Protective role of NHE-3 inhibition in rat renal transplantation undergoing acute rejection

Acute rejection in renal transplantation disturbs solute and volume maintenance in humans accompanied by delayed graft function and poor prognosis. We recently reported that decreased expression and function of Na(+)/H(+) exchanger type 3 (NHE-3) in proximal tubules and epithelial Na(+) channels and aquaporin 2 in collecting ducts are major mechanisms involved in Na(+) and water imbalances shortly after transplantation in rat undergoing acute rejection. We performed kidney transplantations in rats with bilaterally nephrectomized recipients with acute rejection and, in addition, systemically administered a specific inhibitor of NHE-3 (NHE-I). NHE inhibition in acute renal failure was shown to improve tubular function and recovery. The aim of this therapy was to reduce energy consumption of the graft and preserve NHE-3 function. Imbalances in electrolyte excretion declined in NHE-I-treated animals and NHE-3 activity was preserved. Observed NHE-I-dependent changes in electrolyte excretion, polyuria, and reduced protein reabsorption in the acute postoperative phase are predictors of favorable graft outcome in humans.     

HLA配型、交叉反应组(CREGs)误配率与肾移植术后早期排斥反应的关系

目的：探讨人类白细胞抗原（HLA）配型、交叉反应组（CRECs）误配率与尸体肾移植术后早期急性排斥反应的关系。方法：应用泰萨奇单克隆抗体干板进行供受者HLA-Ⅰ类抗原分型；微量序列特异性引物法进行HLA-Ⅱ类基因分型；泰萨奇混合抗原板检测群体反应性抗体（PRA）。结果：PRA阴性131例肾移植患者HLA配型，误配率为6MM、5MM、4MM、3MM、2MM、1MM、0MM的移植例数分别为0、4、26、49、33、15、4，术后早期急性排斥反应发生率分别为0、25％、23．1％、14．3％、12．1％、6．7％、0。CREGs误配率为6MM、5MM时无移植病例。CREGs误配率为4MM、3MM、2MM、1MM、0MM时，排斥反应发生率分别为28．6％、22．9％、9．5％、6．9％、5．5％。结论：HLA配型、交叉组配型可显著提高供受者的HLA相配率，对选择最佳的供者，降低早期急性排斥反应的发生，提高肾移植效果具有重要的意义。     

肾移植急性排斥反应中的TH和Tc类细胞失衡

目的探讨T_H和T_C类细胞的平衡状态及在肾移植急性排斥反应中的作用。方法用流式细胞术检测24例肾移植受者外周血中T_H1/T_H2/T_H3和Tcl/Tc2类细胞的百分率及CD4/CD8比值的动态变化,同时以10例健康成人作对照。结果健康对照组T_H1、T_H2、T_H3及Tcl、Tc2细胞百分率分别为:(10.45±8.15)%、(5.05±4.15)%、(3.90±3.21)%及(9.83±7.03)%、(4.51±2.17)%。肾移植术后稳定组受者外周血T_H1、Tc1细胞百分率[(7.29±5.52)%和(7.04±5.15)%]减低,T_H2、T_H3及Tc2细胞[(6.34±5.67)%、(4.94±4.14)%及(6.86±4.42)%]增多;急性排斥组受者T_H1、Tcl细胞百分率[(18.55±13.21)%和(15.84±11.72)%]增多,T_H2、T_H3及Tc2细胞[(4.19±3.62)%、(3.02±2.83)%和(3.88±1.63)%]减低。急排组、稳定组、健康对照之间的差异均具有统计学意义(P<0.05)。急排组受者CD4/CD8比值(2.24±0.59)较稳定组(1.95±0.45)明显增高。伴随免疫抑制剂的治疗,急排组T_H1、Tcl百分率及CD4/CD8比值减低。结论肾移植受者术后存在T_H1,T_H2/T_H3和Tcl/ Tc2类细胞失衡。T_H1、Tcl类细胞可能通过分泌的IFN-γ在肾移植急性排斥中发挥重要作用,T_H2、T_H3及Tc2类细胞通过所分泌的IL-4和TGF-β等细胞因子诱导了移植后的免疫耐受。     

Pregnancy-induced HLA antibodies respond more vigorously after renal transplantation than antibodies induced by prior transplantation

Acute antibody mediated rejection after HLA-specific antibody incompatible renal transplantation is related to donor specific HLA antibody (DSA) levels. DSA levels may rise sharply after transplant, and aim of this study was to examine changes in DSA levels, particularly according to the primary sensitising event. Changes in 220 HLA specificities in 64 patients over the first 30 days after transplantation were evaluated using microbead assays. The greatest increase from pre-treatment to peak DSA levels was seen in pregnancy-stimulated specificities, median (IQR) increase in MFI of 1981 (94-5870). The next highest increase was for those sensitised by transplant with repeat HLA epitope mismatch, at 546 (-308-2698) (p < 0.01). The difference was especially marked when the pre-treatment antibody level was low; with pre-treatment MFI <1000, peak level was >1000 in 19/26 (73%) of pregnancy stimulated specificities, compared with 9/29 (31%) for all others (p < 0.001). DSA production to specificities stimulated by previous pregnancy was marked, even from very low pre-transplant levels. By contrast, there was a lower rate of antibody resynthesis to specificities repeated from previous transplants, both at antigen and epitope levels.     

Single-center experience with tacrolimus-based immunosuppressive regimens in renal transplantation

The efficacy and safety of tacrolimus (FK506; Prograf) were determined in 28 adult kidney transplant patients (20 males and 8 females), aged 18-68 years (mean+/-S.D.: 46.9+/-4.03 years). Induction therapy was ATG-F (n=23), daclizumab (n=3), or none (n=2), and maintenance immunosuppression consisted of tacrolimus, combined with mycophenolate mofetil (MMF; n=26) or azathioprine (AZA; n=2) and prednisone (Pred). In seven patients, cyclosporine A microemulsion (Neoral) was replaced by tacrolimus for acute rejection (AR; three patients), slow graft function (SGF, two patients) and Neoral side effects (two patients). Acute rejection occurred in five patients (17.8%), three of whom were steroid-resistant treated with a second course of ATG-F. Infection occurred in 10 patients (35.7%) with a total of 15 infectious episodes, comprising bacterial (73%) and viral (27%) infections related to CMV. Other side effects related to tacrolimus were hypertension in four patients (14%) and post-transplantation hyperglycemia in nine patients (32%), three of whom required insulin therapy. In addition, hypercholesterolemia and hypertriglyceridemia occurred in six (21%) and eight patients (28.5%), respectively. The patient's hospital stay was 12.7+/-1.3 days (range: 8-24 days), and mean serum creatinine upon discharge, and at 1, 3 and 6 months following transplantation were: 2.1+/-0.5, 1.47+/-0.21, 1.41+/-0.53 and 1.23+/-0.11 mg/dl, respectively. The 6-month actuarial patient and graft survival rates were 100%. While tacrolimus is an effective calcineurin inhibitor for kidney transplantation (KT), severe acute rejection seen is related to highly sensitized patients, and the CMV infections noted were related to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. Longer follow-up with a larger patient sample is needed to fully assess both the efficacy and safety of tacrolimus, including its metabolic effects.     

Current status of HLA matching in renal transplantation

Summary The impact of HLA compatibility on the success rate of kidney transplants was studied in over 80,000 recipients of primary transplants. The transplants were done from 1982 to 1991 at over 300 transplant centers in 43 countries. The results show that matching the HLA chromosomes in related donor transplants has a striking influence. It is also important that matching for individual HLA antigens in cadaver transplants provides a highly significant improvement in graft survival (P<0.0001). After 5 years, matched grafts have a survival rate approximately 20% higher than completely mismatched grafts. The matching effect is particularly strong in presensitized and second graft recipients. There is now direct evidence that even if it is necessary to transport well-matched kidneys a long way, they have a significantly higher success rate than locally transplanted poorly matched kidneys. New data based on molecular technology show that the precise identification of HLA-DR antigens by DNA typing further improves the success rate of HLA-matched transplants.Abbreviations MM mismatched antigens - RFLP restriction fragment length polymorphism