抗HLA和抗MICA抗体的表达对移植肾功能和急性排斥反应的预示作用

Objective To investigate the prediction of anti-human leukocyte antigen antibodies (HLA) and anti-major histocompatibility complex class I-related chain A antibodies (MICA) to the development of acute rejection (AR) and kidney allograft function. Methods Forty-one kidney transplant patients were prospectively tested for anti-HLA and anti-MICA. Thirty-seven patients were screened using Luminex/single-antigen beads to determine the HLA and MICA-specific antibody levels at 0,30,90, 180,360,720 and 1080 days post-transplantation. The patients and donors of HLA and MICA allele typing were determined by PCR-SSOP, and donor specific antibody (DSA) and non-donor specific antibody (NDSA) were identified.Simultaneously,their serum creatinine (SCr) levels and clinical data were analyzed. Results Nine patients (21.95 % ,9/41 ) had pre-existing anti-HLA and(or) anti-MICA, including 6 cases of anti-MICA,2 cases of anti-HLA, and one case of anti-MICA and anti-HLA. Nine patients had pre-existing DSA and NDSA. In the 37 patients, 6 patients (16.2% ) developed de novo anti-HLA, and 3 (8.1%) developed de novo antiMICA. In patients positive for de novo anti-HLA, the titer of antibody was gradually increased during the follow-up of three years. Four patients out of 9 patients with pre-existing antibodies were suffered from AR (44.4%); In 6 patients positive for de novo anti-HLA,three cases (50.0%) were suffered from AR; In three patients positive for de novo anti-MICA,no AR occurred (P＜0.05). In two patients positive for DSA of HLAⅡ antibody detected at the third and seventh day after transplantation, the renal grafts were renovecd due to rejection. The Scr levels in patients positive for pre-existing MICA with AR were higher than in those positive for pre-existing MICA without AR at each scheduled time point during the follow-up period (P＜0.05). The Scr levels in patients negative for antibodies pre-transplantation and having AR were higher than in those having no AR at each scheduled time point during the follow-up period (P＜0. 01 ). The Scr levels in patients positive for de novo HLA and MICA and having AR one month following transplantation were higher than in those negative for antibodies and having no AR (P＜0.01 ). Conclusion Pre-existing and de novo anti-HLA were the irnportant factors for the development of AR, but the mismatch of HLA and MICA alleles in donors and patients was primary causes for generation of de novo antibodies.     

抗HLA和抗MICA抗体的表达对移植肾功能和急性排斥反应的预示作用

Objective To investigate the prediction of anti-human leukocyte antigen antibodies (HLA) and anti-major histocompatibility complex class I-related chain A antibodies (MICA) to the development of acute rejection (AR) and kidney allograft function. Methods Forty-one kidney transplant patients were prospectively tested for anti-HLA and anti-MICA. Thirty-seven patients were screened using Luminex/single-antigen beads to determine the HLA and MICA-specific antibody levels at 0,30,90, 180,360,720 and 1080 days post-transplantation. The patients and donors of HLA and MICA allele typing were determined by PCR-SSOP, and donor specific antibody (DSA) and non-donor specific antibody (NDSA) were identified.Simultaneously,their serum creatinine (SCr) levels and clinical data were analyzed. Results Nine patients (21.95 % ,9/41 ) had pre-existing anti-HLA and(or) anti-MICA, including 6 cases of anti-MICA,2 cases of anti-HLA, and one case of anti-MICA and anti-HLA. Nine patients had pre-existing DSA and NDSA. In the 37 patients, 6 patients (16.2% ) developed de novo anti-HLA, and 3 (8.1%) developed de novo antiMICA. In patients positive for de novo anti-HLA, the titer of antibody was gradually increased during the follow-up of three years. Four patients out of 9 patients with pre-existing antibodies were suffered from AR (44.4%); In 6 patients positive for de novo anti-HLA,three cases (50.0%) were suffered from AR; In three patients positive for de novo anti-MICA,no AR occurred (P＜0.05). In two patients positive for DSA of HLAⅡ antibody detected at the third and seventh day after transplantation, the renal grafts were renovecd due to rejection. The Scr levels in patients positive for pre-existing MICA with AR were higher than in those positive for pre-existing MICA without AR at each scheduled time point during the follow-up period (P＜0.05). The Scr levels in patients negative for antibodies pre-transplantation and having AR were higher than in those having no AR at each scheduled time point during the follow-up period (P＜0. 01 ). The Scr levels in patients positive for de novo HLA and MICA and having AR one month following transplantation were higher than in those negative for antibodies and having no AR (P＜0.01 ). Conclusion Pre-existing and de novo anti-HLA were the irnportant factors for the development of AR, but the mismatch of HLA and MICA alleles in donors and patients was primary causes for generation of de novo antibodies.     

Luminex技术监测抗HLA抗体对肾移植受者预后的影响

目的探讨Luminex技术检测受者体内抗人类白细胞抗原(HLA)抗体水平在预测肾移植受者预后的价值。方法选取2013年6月至2015年11月在解放军第181医院拟行肾移植患者1 105例(其中354例成功接受肾移植手术),收集肾移植术前、术后血清标本共1 923例次。采用Luminex技术检测术前和术后的抗HLA抗体的阳性率和抗体荧光强度,同时并对移植受者进行移植肾功能检测。结果术前抗HLA抗体阳性血清样本占总数的51.0%(546/1 071),其中抗HLAⅠ类抗体阳性占26.0%(279/1 071),抗HLAⅡ类抗体阳性占24.9%(267/1 071),其中抗HLA抗体Ⅰ、Ⅱ类均为阳性占11.4%(122/1 071)。354例肾移植患者中,术后出现抗HLA抗体者占17%(59/354),其中单独抗HLAⅠ类抗体阳性者25例(术后新发阳性4例),单独抗HLAⅡ类抗体阳性者占15例(术后新发阳性1例),两者皆阳性者19例(术后新发阳性4例)。随访期间,术后抗HLAⅠ类、Ⅱ类及两种抗体均阳性者出现移植肾功能异常者分别为13例、5例和11例,其中术后抗体新发阳性者均出现移植肾功能异常。结论 Luminex技术可动态监测肾移植术后受者抗HLA抗体水平,而抗HLA抗体阳性对预测肾移植受者预后有重要的价值。     

抗HLA和抗MICA抗体的表达对移植肾功能和急性排斥反应的预示作用

目的 探讨抗HLA与抗主要组织相容性复合物Ⅰ类链相关基因A(MICA)抗体的表达对移植肾功能和急性排斥反应的预示作用.方法 采用免疫磁珠流式液相芯片技术检测41例肾移植受者移植前后的抗HLA和抗MICA抗体,其中37例接受了1、3、6个月及1、2、3年的动态随访.分析抗HLA和抗MICA抗体的特异性,及其与血清肌酐和排斥反应的相关性.结果 移植前共有9例(22.0%,9/41)预存抗HLA或(和)抗MICA抗体,其巾抗HLA抗体阳性2例(4.9%,2/41),抗MICA抗体阳性6例(14.6%,6/41),抗HLA和抗MICA抗体均阳性1例(2.4%,1/41).另外有5例抗MICA抗体可疑阳性.除1例的抗MICA抗体为供者特异性抗体(DSA)外,其余均为非供者特异性抗体(NDSA).37例随访者中,6例新生抗HLA抗体(16.2%),3例新生抗MICA抗体(8.1%),新生抗HLA抗体者的抗体滴度在随访3年中呈现上升趋势.9例预存抗体的受者,有4例(44.4%,4/9)发生排斥反应;6例新生抗HLA抗体的受者中,有3例(50.0%)发生急性排斥反应,而3例新生抗MICA抗体的受者均无排斥反应发生,二者间的差异有统计学意义(P＜0.05).新生抗HLA抗体产生较早(术后3 d和7 d)的2例受者均检测到抗HLAⅡ类DSA,其移植肾均因排斥反应而切除.预存抗MICA抗体,且移植后发生排斥反应者在随访的每个时间点上的血清肌酐水平均高于预存抗MICA抗体但无排斥反应者(P＜0.05);移植前抗HLA和抗MICA抗体均阴性者,术后发生排斥反应者在随访的每个时间点上的血清肌酐水平均高于抗体阴性且无排斥反应者(P＜0.01);无论是新生抗HLA抗体还是抗MICA抗体,移植后1个月发生排斥反应者的血肌酐均明显高于抗体阴性且无排斥反应者(P＜0.01).结论 预存和新生抗HLA抗体是移植后发生急性排斥反应的重要因素,而供、受者HLA和MICA基因错配是产生新生抗体的重要原因.     

肾移植术后抗HLA抗体升高对移植肾功能的慢性损害作用

目的 探讨肾移植术后抗HLA抗体升高对移植肾功能的慢性损害作用.方法 采用免疫荧光液相芯片技术检测57例肾移植术后半年以上受者的抗HLA抗体水平,根据抗HLA抗体水平的不同,将受者分为抗HIA抗体(≥10%)阳性组和抗HLA抗体(＜10%)阴性组.再根据阳性组中抗HLA抗体类别的不同,将受者分为抗HLA-Ⅰ类抗体阳性、Ⅱ类抗体阴性(Ⅰ+Ⅱ+)组,抗HLA-Ⅰ类、Ⅱ类抗体均阳性(Ⅰ+Ⅱ+)组和抗HLA-Ⅰ类抗体阴性、Ⅱ类抗体阳性(Ⅰ-Ⅱ+)组.观察和比较各组受者的临床资料和血肌酐(Cr)水平,并进行统计学分析.结果 57例受者中,抗HLA抗体阴性组41例(71.9%),阳性组16例(28.1%);阳性组中,Ⅰ+Ⅱ-组和Ⅰ+Ⅱ+组受者各3例,I-II'组10例.抗HLA抗体阴性组和阳性组受者的肾移植术后时间分别为(4.55±3.16)年和(6.64±3.66)年(P＜0.5),随着术后时间的延长,抗HLA抗体阳性者呈上升趋势.抗HLA抗体阴性组有13例(31.7%)血Cr异常,平均血Cr水平为(92.12±27.52)μmol/L;阳性组有13例(81.3%)血Cr异常,平均血Cr水平为(191.1±119.95)μmaol/L,其中又以Ⅰ+Ⅱ+组的受者血Cr水平最高,为(213.00±165.38)μmol/L,与抗HLA抗体阴性组比较,差异有统计学意义(P＜0.05).结论 抗HLA抗体升高是影响肾移植预后的重要标志物;尤其是抗HLA-Ⅱ类抗体升高对移植肾功能有慢性损害作用.     

肾移植受者术前测定抗HLA-IgG抗体的临床意义

目的　研究肾移植受者术前抗HLA IgG抗体水平的临床意义。 方法　采用酶联免疫吸附法 (ELISA)检测 184例肾移植受者术前抗HLA IgG抗体水平。分析抗HLA IgGI类抗体、Ⅱ类抗体阳性与急性排斥反应发生的关系。结果　肾移植受者术前抗HLA IgG抗体阴性者 15 5例 ,其中18例发生排斥反应 ,发生率 11.6 % ;抗HLA IgGⅠ类抗体阳性者 7例 ,2例发生排斥反应 ,发生率2 8.5 7% ;抗HLA IgGⅡ类抗体阳性者 9例 ,4例发生排斥反应 ,发生率4 4 .4 4 % ;Ⅰ类抗体、Ⅱ类抗体均阳性者 13例 ,8例发生排斥反应 ,发生率 6 1.5 3% ,与阴性对照组比较 ,差异有显著性 (P <0 .0 0 1)。结论　肾移植受者术前抗HLA IgG抗体阳性与术后排斥反应发生率密切相关 ,提示术前检测抗HLA IgG抗体具有重要的临床意义 ,可以预测排斥反应及指导治疗。     

致敏受者移植肾存活率和抗HLA抗体的临床观察

目的观察致敏受者与非致敏受者移植肾存活率的差别,以及移植肾功能与抗HLA抗体变化的关系。方法纳入中山大学附属第一医院器官移植中心2000年4月至2008年12月间行肾移植后资料完整受者1309例。根据受者术前ELISA检测群体反应性抗体（PRA）的结果将受者分为50%≤PRA≤100%组（n=35）、10%≤PRA〈50%组（n=47）和PRA〈10%组（n=1227）。所有供受者采用PCR序列特异性引物进行HLA分型。运用标准HLA配型和氨基酸残基配型。采用Kaplan-Meier法对3组受者术后存活率进行组间生存分析。分析肾移植后抗HLA抗体的变化及其与移植肾功能和HLA错配的关系。结果随着随访时间增加,3组移植肾累积存活率均有下降。在术后3年内3组移植肾存活率差异较小（P〉0.05）,3年后3组移植肾存活率差异有统计学意义（P〈0.05）。10%≤PRA≤100%受者移植肾累积存活率显著低于PRA〈10%受者（P〈0.05）,50%≤PRA≤100%受者移植肾累积存活率也显著低于10%≤PRA〈50%受者（P〈0.05）。12例移植肾失功的受者中7例（58.3%）出现抗体增强,62例移植肾功能正常的受者中仅8例（12.9%）出现抗体增强,两者差异有统计学意义（P〈0.05）。出现新生抗体的受者抗体谱中,大多数包含有针对错配抗原的抗HLA抗体。结论无论是供者特异性还是非供者特异性抗体,抗HLA抗体的存在及其效价都会影响移植肾的存活。术后抗HLA抗体的变化与移植肾功能有关。     

在移植肾功能稳定的受者中主动撤除环孢素A的临床研究

目的 研究在移植肾功能稳定的受者中主动撤除环孢素A(CSA)对急性排斥反应发生率及肾功能的影响.方法 选择35例肾功能稳定的肾移植受者,其中尸体肾移植23例,亲属活体肾移植12例.除2例为再次肾移植外,其余均为初次肾移植.分别在肾移植术后6个月～6年时停用CsA,平均为术后(13.3±9.1)个月.撤除CsA后免疫抑制方案为:霉酚酸酯(MMF)+西罗莫司(SRL)+泼尼松(Pred).撤除CsA前有9例做了移植肾穿刺活检,8例测定了抗HLA抗体.结果 对35例受者随访6个月～4.5年,平均14.8个月.撤除CsA前、后血肌酐平均值分别为(88.1±15.5)μmol/L和(92.3±23.7)/μmol/L(P0.05).撤除CsA后,有2例经活检证实发生急性排斥反应,治疗后均逆转;CsA所致的毒副作用,如牙龈增生、糖耐量异常和多毛症等明显改善.9例移植肾活检中,有3例肾功能正常的受者已出现轻度慢性移植肾肾病表现.抗HLA抗体检测中,7例阴性者在撤除CsA前、后肾功能无明显变化.1例抗HLA抗体呈强阳性者在撤除CsA后进展为慢性移植肾肾病,恢复血液透析.结论 对移植肾功能稳定的受者在移植6个月后撤除CsA,转换为"霉酚酸酯+西罗莫司+泼尼松"的免疫抑制方案是安全的,不增加急性排斥反应风险;撤除CsA有利于消除一些与其相关的毒副作用;对抗HLA抗体呈强阳性者.撤除CsA后很难改变肾功能的进展.     

抗人类白细胞抗原抗体对肾移植术后长期存活受者移植肾功能的影响

目的研究抗HLA抗体对肾移植术后长期存活受者移植肾功能的影响。方法回顾性分析1993至2006年于首都医科大学附属北京友谊医院行肾移植,并于2007年检测抗HLA抗体为阳性的143例受者临床资料。受者均于2010至2011年再次检测群体反应性抗体,观察肾功能和存活情况。结果 143例受者中,抗HLA-Ⅰ类抗体阳性13例,抗HLA-Ⅱ类抗体阳性107例,抗HLA-Ⅰ+Ⅱ类抗体阳性23例。截至2014年10月,上述3组抗体阳性受者中,移植肾失功和肾功能下降受者比例分别为61.5%(8/13)、42.0%(45/107)和87.0%(20/23)。3种类型抗体阳性受者发生肾功能异常比例差异具有统计学意义(χ2=14.3,P0.05),抗HLA-Ⅱ类抗体阳性受者中肾功能异常比例低于抗HLA-Ⅰ+Ⅱ类抗体阳性受者,差异有统计学意义(χ2=15.3,P0.017)。结论抗HLA-Ⅰ+Ⅱ类抗体对长期存活受者的移植肾功能影响大于抗HLA-Ⅱ类抗体。     

抗人类白细胞抗原与抗组织相容性Ⅰ类相关链A位点特异性抗体对移植肾功能的监测价值

目的 探讨抗人类白细胞抗原(HLA)与抗主要组织相容性Ⅰ类相关链A位点(MI-CA)抗体在移植肾功能中的意义.方法 采用免疫磁珠流式液相芯片技术检测135例等待肾移植患者中的抗HLA和抗MICA抗体,其中33例.肾移植患者接受了2年的动态随访;采用PCR-SSOP方法 进行HLA和MICA基因分型并鉴定供者特异性抗体(DSA)和非供者特异性抗体(NDSA),结合血清肌酐水平和临床资料进行分析.结果 34.1%等待肾移植患者(46/135)预存抗HLA和抗MICA抗体.动态随访33例肾移植患者:20例患者移植前后抗体均阴性;10例患者移植前后抗体阳性且类型未改变;3例患者移植6个月后产生新生抗体(9.1%).2例移植前抗体阴性,移植后6个月新生A33、A31和DQ7、DR17、DR18为NDSA抗体,移植后1、2年新生DR12和DR11为DSA抗体;1例移植后1年新增MICA27和MICA02特异性抗体的同时新生HLA-B41、A32抗体.在33例肾移植患者中,抗体阳性组患者与抗体阴性组比较差异有统计学意义(P＜0.05);MICA抗体阳性组患者的血清肌酐水平升高更明显(P＜0.01).结论 无论肾移植前患者是否预存抗HLA和抗MICA抗体,移植后动态监测抗HLA和抗MICA特异性抗体的变化,对预警排斥反应的发生和指导临床治疗来防止移植肾功能减退均具有一定价值.     

Significance of HLA-matching and anti-HLA antibodies in heart transplant patients receiving induction therapy?

ObjectivesThough Human Leukocyte Antigen (HLA) matching benefits are demonstrated in renal transplantation, evidence in heart transplantation is lacking, and its clinical feasibility is uncertain. Post-transplantation anti-HLA antibodies are being increasingly studied in organ transplantation, with diverging conclusions between transplantated organs.MethodsWe analyzed retrospectively the influence of HLA matching and anti-HLA antibodies on overall survival, acute rejection and chronic allograft vasculopathy in 309 patients receiving induction therapy and triple-drug immunosuppression.ResultsThe average number of HLA-A/B/DR mismatches between donor and recipient was 4.9 ± 1. The majority of mismatches was for Class I HLA-A/B with an average of 3.3, then for Class I HLA-DR with an average of 1.6. Overall, the HLA-A/-B/-DR mismatches had no influence on the cardiac allograft survival (p = 0.28). However, HLA-DR mismatches were negatively correlated to severe cellular and/or humoral allograft rejection (p = 0.04). Our analysis found anti-HLA antibodies in 27% of recipients, de novo anti-HLA antibodies in 16% of recipients, and donor-specific anti-HLA (DSA) antibodies in 8% of recipients. Furthermore, de novo DSA had no influence on the 5-year survival (78% with DSA vs. 92% without DSA; p = 0.49), which may be masked by the limited number of recipients in analysis By univariable analysis, anti-HLA antibodies (preexisting or de novo) unrelated or related to the donor had no influence on severe cellular and/or humoral rejection or on chronic allograft vasculopathy.ConclusionsHLA-DR mismatch was negatively correlated to severe cellular and/or humoral allograft rejection but had no influence on cardiac allograft survival. In this study, anti-HLA antibodies (preexisting or de novo) unrelated or related to the donor had no influence on cellular and/or humoral rejection or on chronic allograft vasculopathy. The results of this study add to the controversy on the impact of allo-antibodies in heart transplant recipients receiving induction therapy and contemporary immunosuppression.     

Association of De Novo Human Leukocyte Antigen and Major Histocompatibility Complex Class I Chain-Related Gene-A Antibodies and Proteinuria With Graft Survival 5 Years After Renal Transplantation

Background

Association of de novo human leukocyte antigen (HLA) and major histocompatibility complex class I chain-related gene-A (MICA) antibodies and proteinuria with graft survival 5 years after renal transplantation. De novo presence of HLA and MICA antibodies after renal transplantation is associated with poor graft survival. Proteinuria after transplantation is also considered a risk factor for premature graft loss. In this study, we investigated the association of de novo HLA and MICA antibodies on proteinuria after renal transplantation and the association of proteinuria and de novo antibodies with graft survival.

Methods

We enrolled 275 patients without preexisting HLA and MICA antibodies followed for >5 years after renal transplantation. All donor organs were from living-related donors or from an organ donation program. HLA and MICA antibodies were detected by the Luminex method. Patients with proteinuria (>150 mg/d) underwent intermittent 24-hour proteinuria examination.

Results

The frequencies of de novo HLA and MICA antibody 5 years after transplantation were 25.8% and 12%, respectively. In total, 26.5% of patients had proteinuria at the 5-year follow-up. De novo HLA antibody was associated with increased proteinuria after transplantation (relative risk, 3.12). HLA antibody and proteinuria were both associated with poor 5-year graft survival (P = .027 and P = .006, respectively).

Conclusion

De novo HLA and MICA antibodies and proteinuria after renal transplantation are all associated with poor graft survival. De novo HLA antibody is independent risk factor for posttransplant proteinuria, and proteinuria affects the association of de novo antibodies with decreased graft survival after transplantation.     

Development of posttransplant antidonor HLA antibodies is associated with acute humoral rejection and early graft dysfunction

BACKGROUND: The goal of this study was to determine whether the production of posttransplant antibodies directed against donor HLA mismatches (donor specific antibody; DSA) is associated with renal allograft rejection and early graft dysfunction. METHODS: Forty-nine adult renal allograft recipients with increased risk of rejection were enrolled during the period of October 2001 through May 2003 and were prospectively monitored for the development of anti-HLA antibodies. RESULTS: Of 49 patients, eight (16.3 %) patients were diagnosed with acute humoral rejection (AHR) and 11/49 (22.4%) patients were diagnosed with acute cellular rejection (ACR). A strong association between pretransplant HLA sensitization and AHR was found (P=0.005). Of the eight patients diagnosed with AHR, the majority developed DSA before or concomitant with episodes of rejection (P<0.001). Only 3 of 41 patients (7.3%) without AHR developed DSA. The pathogenic role of alloantibodies was further substantiated by analyzing their association with graft function as measured by serum creatinine levels. The average serum creatinine after the third month posttransplantation in DSA producers was 2.24+/-1.01 mg/dL, while in non-DSA patients the average serum creatinine was 1.41+/-0.37 mg/dL (P<0.01). CONCLUSION: This study reveals a strong association between the production of DSA, AHR, and early graft dysfunction. Our findings indicate that prospective monitoring for anti-HLA antibodies following transplantation is a useful test for the diagnosis and classification of AHR for identifying patients at risk of early graft dysfunction.     

The presence of HLA-directed antibodies after heart transplantation is associated with poor allograft outcome

BACKGROUND: The clinical significance of HLA-directed antibodies newly detected after transplantation (HT) is controversial. METHODS: Seventy-one HT recipients consented to enroll. Mean follow-up time was 28 months (range 6-48). Panel reactive antibody (PRA) analysis was performed on posttransplant sera (2 weeks, 1, 2, 3, 6, and 12 months and annually thereafter) using Flow-PRA. A mean of 6.9+/-1.2 serum samples per patient were obtained. Severity of cellular rejection was measured using the ISHLT grading system. Coronary angiography and intravascular ultrasound (IVUS) studies were performed annually to evaluate severity of allograft vasculopathy. RESULTS: Twenty-five recipients had newly detected HLA-directed antibodies during the first year postHT. HLA class I antibodies were detected in 18 patients (25.4%), and class II in 11 patients (15.5%). The majority of donor recipient pairs were HLA mismatched (4.6+/-1.2 of the six major HLA antigens). Only mismatches at HLA-A locus had significant association with de novo posttransplant antibody formation. Length of ischemia time was correlated with early and sustained presence of de novo HLA-directed antibodies postheart transplant. Importantly, an association between de novo HLA-directed antibodies and cellular rejection was notes (P=0.0002). De novo HLA class II directed antibodies are also associated with IVUS documented vasculopathy (P<0.002). Finally, death due to allograft failure is associated with the presence of de novo formed HLA class II directed antibodies (P=0.008). CONCLUSIONS: Identifying the formation of de novo HLA-directed antibodies following heart transplantation may predict allograft outcome. This, in turn, may serve as a tool for individualization of immunosuppression protocols in heart transplant recipients.     

动态分析HLA和MICA特异性抗体对移植肾功能的影响

目的 探讨肾移植前后人类白细胞抗原(HLA)和主要组织相容性一类相关链A基因(MICA)抗体特异性对移植后排斥反应和移植肾功能的影响. 方法采用免疫荧光液相芯片技术检测27例肾移植(尸供22例,亲属活体供肾5例)受者手术前后抗HLA抗体和MICA抗体的特异性和阳性值变化,并结合供受者的基因分型,区分供体特异性抗体和非供体特异性抗体.取同期的临床资料和SCr水平进行分析. 结果 27例移植患者中带肾存活26例,移植肾失功1例.移植后1、3、6、12个月时动态随访24例,失访2例.27例患者移植前预存抗体7例(25.9%),其中HLA抗体阳性2例、MICA抗体阳性3例,HLA和MICA抗体均阳性2例.肾移植前HLA和MICA抗体均阴性者中移植后3～6个月产生新生抗体3例.1例新生HLA-Ⅱ类特异性抗体者,移植半年后出现慢性排斥反应,经治疗术后1年SCr>200 btmol/L.3例肾移植前MICA抗体阳性者,术后MICA抗体的特异性均无改变,但抗体的阳性分值呈现2～8分的变化,1年后均升高到移植前(4～8分)水平.移植前预存低阳性率HLA-Ⅱ类特异性抗体者1例,移植后2周有发热等排斥反应,巨细胞病毒检测阳性,移植后1个月时SCr为171μmol/L,3个月升高到236μmol/L.24例分为抗体阴性组(14例)和抗体阳性组(10例).移植后1个月和1年时SCr水平2组间比较差异有统计学意义(P=0.03,0.05). 结论 移植后3～6个月是新生抗体变化的重要随访时间,可根据HLA和MICA抗体的特异性和阳性分值变化,尽早采取有效方法预防排斥反应和减少移植肾功能减退的发生和发展.     

Longitudinal profile of circulating T follicular helper lymphocytes parallels anti‐HLA sensitization in renal transplant recipients

Antibody‐mediated rejection is responsible for 30%‐50% of renal graft failures. Differentiation of B cells into antibody‐producing plasmablasts depends on the collaboration of follicular helper T cells (Tfh). We analyzed circulating Tfh (cTfh) in kidney recipients and studied cTfh relationship with anti‐HLA antibody production and graft outcome. cTfh were longitudinally analyzed in a prospective cohort of patients (n = 206), pre‐ and posttransplantation. Clinical data, HLA sensitization, and cTfh function were recorded. Both pretransplant and 6‐month posttransplant cTfh were able to derive IgG‐producing plasmablasts. Pretransplant cTfh was decreased in patients, especially in those who received dialysis. However, these cells were increased in patients with previous allograft or transfusions and in HLA‐sensitized recipients. After transplantation cTfh expanded, significantly more in patients who developed de novo anti‐HLA antibodies than in patients who remained unsensitized. Augmented pretransplant cTfh positively correlated with higher intensity of pretransplant anti‐HLA class I and with de novo anti‐HLA class I and anti‐HLA class II antibodies. Consistently, pretransplantation cTfh were higher in patients who experienced acute rejection (HR = 1.14 [1.04‐1.25]). Thus, we show a role for Tfh in anti‐HLA sensitization and rejection. Multicenter studies with additional patient cohorts are needed to validate these results. Immunosuppressive drugs targeting Tfh could be useful to improve outcomes.     

HLA class I sensitization in islet transplant recipients: report from the Collaborative Islet Transplant Registry

Pancreatic islet transplantation is a promising treatment option for patients severely affected with type 1 diabetes. This report from CITR presents pre- and posttransplant human leukocyte antigen (HLA) class I sensitization rates in islet-alone transplantation. Data came from 303 recipients transplanted with islet-alone between January 1999 and December 2008. HLA class I sensitization was determined by the presence of anti-HLA class I antibodies. Panel-reactive antibodies (PRA) from prior to islet infusion and at 6 months, and yearly posttransplant was correlated to measures of islet graft failure. The cumulative number of mismatched HLA alleles increased with each additional islet infusion from a median of 3 for one infusion to 9 for three infusions. Pretransplant PRA was not predictive of islet graft failure. However, development of PRA >20% posttransplant was associated with 3.6-fold (p < 0.001) increased hazard ratio for graft failure. Patients with complete graft loss who had discontinued immunosuppression had significantly higher rate of PRA ≥ 20% compared to those with functioning grafts who remained on immunosuppression. Exposure to repeat HLA class I mismatch at second or third islet infusions resulted in less frequent development of de novo HLA class I antibodies when compared to increased class I mismatch. The development of HLA class I antibodies while on immunosuppression is associated with subsequent islet graft failure. The risk of sensitization may be reduced by minimizing the number of islet donors used per recipient, and in the absence of donor-specific anti-HLA antibodies, repeating HLA class I mismatches with subsequent islet infusions.     

The presence of donor-specific antibodies in renal transplantation

Determining the presence of anti-HLA antibodies before transplantation is an important factor to prevent loss of function among renal transplantations. In addition, recent studies have shown that not only the pretransplantation existence of anti-HLA antibody but also posttransplantation donor-specific antibodies (DSA) and non-donor-specific antibodies are significantly associated with allograft rejection or loss of graft function. This study presented DSA among patients after renal transplantation together with graft function and survival.