抗体介导的排斥反应研究中的热点问题

由于供者特异性抗体（donor specific antibody,DSA）检测技术的突破,移植后产生的抗体对移植物的作用越来越受到重视。大量证据证明了抗体与排斥反应尤其是慢性排斥反应之间的因果关系。我们就器官移植后抗体介导的排斥反应（antibody—mediated rejection,AMR）研究中的几个热点问题讨论如下。     

移植肾慢性活动性抗体介导排斥反应的研究进展

有效控制排斥反应是临床肾移植获得成功的基石之一。结合临床和病理学表现,排斥反应的经典类型包括超急性排斥反应、加速性排斥反应、急性排斥反应和慢性排斥反应^([1-2])。随着Banff分类的更新,2005年依据效应机制的不同,将排斥反应分为T细胞介导的排斥反应(T cell mediated rejection,TCMR)和抗体介导的排斥反应(antibody mediated rejection,AMR)^([3])。     

抗体介导的排斥反应与临床（附视频）

随着器官移植体液免疫理论的发展与抗体检测技术的进步,抗体介导的排斥反应（AMR）已逐渐被认识和引起关注。其治疗难度大、逆转率较低,已成为导致移植物失功的重要原因。本文较为系统地介绍了AMR的免疫机制、诊断与防治进展,以及供者特异性抗体的检测技术和临床意义,从而提出供者特异性抗体是引起移植物排斥反应特别是慢性排斥反应的主要原因,移植受者需常规监测抗体以利及时干预和治疗。     

抗体介导的排斥反应与临床

随着器官移植体液免疫理论的发展与抗体检测技术的进步,抗体介导的排斥反应(AMR)已逐渐被认识和引起关注。其治疗难度大、逆转率较低,已成为导致移植物失功的重要原因。本文较为系统地介绍了AMR的免疫机制、诊断与防治进展,以及供者特异性抗体的检测技术和临床意义,从而提出供者特异性抗体是引起移植物排斥反应特别是慢性排斥反应的主要原因,移植受者需常规监测抗体以利及时干预和治疗。     

抗体介导的排斥反应病理学研究概要

抗体介导的排斥反应（AMR）是近来获得公认的导致移植物失功能的主要因素,其临床诊断需要结合移植物功能检测、受者血清供者特异性抗体检测和移植物活组织检查病理学观察及C4d免疫组织化学染色予以综合判断。其中病理学诊断是不可或缺的手段。本文简述了AMR近来的研究历程和其在主要移植器官内的基本病理学变化特征。移植肾、心脏等主要移植器官发生AMR时可见明显的毛细血管床部分C4d沉积,而移植肝往往C4d沉积不明显。鉴于临床C4d阴性AMR,近来研究较多集中于利用蛋白组学等现代分子生物学技术协助诊断AMR和寻找新的诊断标志物,移植肝AMR特殊病理学特征如中央静脉炎的意义和C3d、C4d协同染色在移植心脏AMR诊断中的作用。     

肾移植抗体介导排斥反应的研究进展

近年来,移植外科、移植病理学以及移植免疫学的研究均取得了令人瞩目的进步,促进了人们对器官移植排斥反应机制、诊断及治疗的认识不断提高。20世纪90年代初,Halloran等（[1-2]）确立了人类白细胞抗原（human leukocyte antigen,HLA）抗体在移植肾排斥反应损伤中的重要作用。     

移植肾抗体介导的排斥反应的发病机制研究进展

抗体介导的排斥反应(AMR)是移植肾排斥反应的一种重要类型,也是导致移植肾丢失的首要原因。与T细胞介导的排斥反应相比,AMR临床症状重、救治困难、预后差,越来越受到移植科医师的重视。本文就AMR的发病机制进行综述,从抗体生成、免疫激活、移植肾功能障碍等方面简要介绍相关研究进展。     

移植肾抗体介导的排斥反应的病理学

抗体介导的排斥反应（AMR）亦称体液性排斥反应,是由抗体、补体等多种体液免疫效应因子参与所致的排斥反应免疫损伤。AMR在超急性排斥反应、急性排斥反应以及慢性排斥反应中均发挥了重要的致病作用。本文对AMR的基本定义、Banff移植病理学诊断标准（Banff标准）中AMR病理学的研究历程及其主要成果以及移植肾AMR的主要病变特征进行综述,旨在为准确诊断、及时治疗AMR提供依据,以保障移植肾和受者的长期存活。     

硼替佐米治疗多发性骨髓瘤患者的护理

应用硼替佐米治疗5例多发性骨髓瘤患者,给药前做好心理护理,给药时密切监护并观察不良反应,包括低血压、乏力、消化道反应、血小板减少、中性粒细胞减少和周围神经感觉异常,经采取相应护理措施,患者均完成药物治疗,其中1例完全缓解,4例部分缓解.均未发生与护理相关的不良反应.     

抗体介导的小鼠肾移植急性排斥反应动物模型

抗体介导的排斥反应(AMR)是影响远期移植肾存活的首要原因, 相关领域的研究正成为热点。小鼠肾移植急性AMR模型可应用于研究移植肾AMR的发生机制、诊断标识、预防和治疗策略。目前国际上已报道数种小鼠肾移植急性AMR模型的建立方法, 但国内尚缺乏相关研究。本文对小鼠肾移植急性AMR模型的建立方法作一总结, 并对该模型的特点及未来可能的发展趋势加以探讨, 为需要应用这一模型的研究者提供参考。     

De Novo HLA Sensitization and Antibody Mediated Rejection Following Pregnancy in a Heart Transplant Recipient

Here we report a case wherein both donor-specific and third-party, paternal, HLA class II specific antibodies developed following a spontaneous miscarriage resulting in antibody-mediated rejection in a patient who had undergone an orthotopic cardiac transplant six years earlier.     

Bortezomib for Acute Antibody‐Mediated Rejection in Liver Transplantation

Antibody‐mediated rejection (AMR) is an uncommon, but challenging type of rejection after solid organ transplantation. We review three cases of AMR in ABO‐compatible liver transplant recipients. These cases were characterized by severe acute rejection resistant to steroids and antithymocyte globulin, histologic evidence of plasma cell infiltrates, C4d positivity and high serum anti‐HLA donor‐specific antibodies. All three patients were treated with bortezomib, a proteasome inhibitor effective in depleting plasma cells. After treatment, all patients had improved or normal liver function tests, resolution of C4d deposition and significant decline in their HLA donor‐specific antibodies.     

Clinical Relevance of Preformed HLA Donor-Specific Antibodies in Kidney Transplantation

This study analyzes the influence of preformed DSA, identified by HLA-specific ELISA assays, on graft survival and evaluates the incidence of antibody-mediated rejection (AMR) in patients with and without pregraft desensitization.
Kidney graft survival at 8 years was significantly worse in patients with DSA (n = 43) than in those without DSA (n = 194)(p = 0.03). The incidence of AMR in patients with DSA is 9-fold higher than in patients without DSA (p < 0.001) and their graft survival is significantly worse than in DSA patients without AMR and in non-DSA patients (p = 0.005). The prevalence for AMR in patients with DSA detected on historic serum is 32.3% in nondesensitized patients and 41.7% in desensitized patients. The risk for AMR is significantly more elevated in patients with strongly positive DSA (score 6–8) compared to those with DSA score 4 (p < 0.001), and in patients with historic DSA+/CXM+ compared to those with DSA+/CXM− (p = 0.01).
The presence of preformed DSA is strongly associated with graft loss in kidney transplants, related to an increased risk of AMR. Our findings demonstrate the importance of detection and characterization of DSA before transplantation. Stratification of this risk could be used to determine kidney allocation and to devise specific strategies for these patients.     

Acute and Chronic Vascular Rejection in Nonhuman Primate Kidney Transplantation

A nonhuman primate (NHP) study was designed to evaluate in nonlife-supporting kidney allografts the progression from acute rejection with transplant endarteritis (TXA) to chronic rejection (CR) with sclerosing vasculopathy. Group G1 (n = 6) received high cyclosporine A (CsA) immunosuppression and showed neither TXA nor CR during 90 days post-transplantation. Group G2 (n = 6) received suboptimal CsA immunosuppression and showed severe TXA with graft loss within 46 days (median). Arterial intimal changes included infiltration of macrophages and T lymphocytes (CD3, CD4, CD8) with few myofibroblasts, abundant fibronectin/collagen IV, scant collagens I/III, high rate of cellular proliferation and no C4d accumulation along peritubular capillaries. Group G3 (n = 12) received suboptimal CsA and anti-rejection therapy (rabbit ATG + methylprednisolone + CsA) of TXA. Animals developed CR and lost grafts within 65 days (median). As compared to G2, the arterial intimal changes showed less macrophages and T lymphocytes, an increased number of myofibroblasts, abundant fibronectin/collagen IV and scar collagens I/III, C4d deposition along capillaries in 60% of animals and transplant glomerulopathy in 80% of animals. In conclusion, CR is an immune stimulated process initiated during TXA with the accumulation and proliferation of myofibroblasts, and progressive deposition of collagens in the intima. Our experimental design appears well suited to study events leading to CR.     

Acute Antibody-Mediated Rejection Following Heart Transplantation

Acute antibody-mediated rejection (AMR) in heart transplantation is often associated with hemodynamic compromise, and is associated with increased mortality and development of accelerated transplant coronary artery disease (TCAD). The diagnosis of AMR has historically been controversial and outcomes with aggressive immunosuppressive therapy including plasmapheresis and cyclophosphamide are poor. Advances in diagnostic techniques like the demonstration of immunopathologic evidence for antibody-mediated rejection by deposition of the complement split product C4d in tissue and detection of anti-HLA antibodies by flow cytometry will assist in further characterizing AMR. Immunosuppression targeting B-lymphocytes and use of m-TOR inhibitors to alter the predilection to develop TCAD and improve survival in AMR remains to be proven.     

骁悉(MMF)预防肾移植术后急性排斥的临床观察

应用新型免疫抑制剂MMF预防肾移植术后急性排斥进行随机对照临床观察。MMF应用组11例,对照组10例。随访十二个月以上,排斥均有病理证实。结果提示;MMF组发生急性排斥仅占9％(1/11),经小剂量激素冲击逆转。对照组发生急性排斥占30％(3/10),2例为难治性排斥,经大剂量激素、OKT_3治疗无效后改用MMF,急性排斥逆转,肾功能恢复正常,1例细胞性排斥经大剂量激素冲击治愈。对照组1例肝胰损害患者改用MMF后治愈。临床研究表明MMF具有预防和减少急性排斥发生的效果而且有抗难治性排斥的作用,还具有对CsA有严重并发症者的补救作用,MMF的安全性稳定。副作用主要是腹泻,减药可缓解。     

Utility of HLA Antibody Testing in Kidney Transplantation

HLA antigens are polymorphic proteins expressed on donor kidney allograft endothelium and are critical targets for recipient immune recognition. HLA antibodies are risk factors for acute and chronic rejection and allograft loss. Solid-phase immunoassays for HLA antibody detection represent a major advance in sensitivity and specificity over cell-based methods and are widely used in organ allocation and pretransplant risk assessment. Post-transplant, development of de novo donor–specific HLA antibodies and/or increase in donor-specific antibodies from pretransplant levels are associated with adverse outcomes. Although single antigen bead assays have allowed sensitive detection of recipient HLA antibodies and their specificities, a number of interpretive considerations must be appreciated to understand test results in clinical and research contexts. This review, which is especially relevant for clinicians caring for transplant patients, discusses the technical aspects of single antigen bead assays, emphasizes their quantitative limitations, and explores the utility of HLA antibody testing in identifying and managing important pre- and post-transplant clinical outcomes.     

Therapy Modalities for Antibody Mediated Rejection in Renal Transplant Patients

Introduction: The aim of our study was to determine the effectiveness of immunoglobulin, rituximab and plasmapheresis in renal transplant patients with antibody mediated rejection (AMR). Patients and Methods: Fourteen renal transplant patients with AMR were included in this study. The mean age of the patients was 33.9 ± 10.3 years and 10 (71.4%) of them were male. Lymphocyte cross match was negative for all patients and 10 (71.4%) of them were living donor transplants. Six patients were administered tacrolimus, three patients cyclosporine, two patients everolimus, and three patients sirolimus for immunosuppression. The patients with AMR were administered IVIG, rituximab and plasmapheresis. Results: Patient survival rate was 100%, graft survival rate after AMR was 50% in the first year and 33% in the 2nd and third years. AMR developed 31.9 ± 25.9 months after transplantation. Seven (50%) patients lost their grafts. Delayed graft function was observed in 28.6%, chronic allograft dysfunction in 78.5%, diabetes after transplantation in 14.3%, and cytomegalovirus infection in 7.1% of the patients. At the last follow-up, the mean blood creatinine was 3.1 ± 1.4, the mean proteinuria was 2300 (1300–3300) mg/day and the mean GFR was 34.5 ± 17.6 ml/min. C4d was positive in peritubullar capillaries in all patients, while neutrophil accumulation in peritubular and glomerular capillaries was observed in 8 patients. Chronic allograft vasculopathy was observed in 12 patients. Conclusion: AMR leads to progressive loss of renal function and has low graft survival. More effective treatment alternatives are needed for this clinical issue.