胆红素在移植领域的研究进展

器官移植和细胞移植是目前治疗终末期器官衰竭的有效方法,然而移植后长期的免疫抑制治疗容易导致感染和肿瘤的发生.另外,各类免疫抑制剂对缺血再灌注损伤和移植后慢性排斥反应的抑制作用不明显,甚至无效[1].如何控制排斥反应、减少缺血再灌注损伤以及诱导免疫耐受逐渐成为移植领域血受关注的问题.     

大鼠小肠移植慢性排斥反应模型的建立

随着移植免疫学研究的进展及新型免疫抑制剂的问世,近年来器官移植取得了很大进步,尤其在小肠移植方面也有了长足发展.但是观察发现,随着器官移植存活期的延长,出现了移植物功能逐渐减退直至丧失的现象.目前研究认为,造成这种移植物远期功能减低的主要原因就是慢性排斥反应[1].因此,我们成功地建立了大鼠小肠移植慢性排斥反应模型,为临床研究慢性排斥反应提供了平台.     

移植小肠病理学诊断标准及其进展

小肠移植已经成为肠衰竭最为理想的治疗方式.现代临床小肠移植包括3种类型:单独小肠移植、肝小肠联合移植和腹腔多器官簇移植.移植小肠具有与其它实体移植器官显著不同的免疫学和解剖生理学特点,导致移植小肠出现显著的急性排斥反应、慢性排斥反应、移植物抗宿主病(GVHD)、感染和移植后淋巴组织增生性疾病(PTLD)等诸多独特且严重...     

移植肾慢性排斥反应患者治疗前后24h尿蛋白定量、血肌酐及血压水平变化研究

目的 探讨移植肾慢性排斥反应患者治疗前后24h尿蛋白定量、血肌酐及血压水平变化情况.方法 选取行肾移植术后发生移植肾慢性排斥反应的70例患者为实验组,并选取同期行肾移植术后不伴移植肾慢性排斥反应的正常患者70例为对照组.对于发生排斥反应的患者给予冲击治疗和调整免疫抑制剂的剂量逆转排斥反应.将两组患者行肾移植术后的和出院前的24h尿蛋白定量、血肌酐及血压进行研究比较.结果 经研究发现,治疗前实验组的24h尿蛋白定量、血肌酐及血压水平明显高于对照组,治疗后降低为基本正常,有显著性差异或有非常显著性差异(P＜0.01).结论 移植肾慢性排斥患者的24h尿蛋白定量、血肌酐及血压水平变化呈现一定的规律性,抗排斥反应治疗可大大改善其水平.研究证明24h尿蛋白定量、血肌酐及血压水平对移植肾慢性排斥反应的临床诊断和治疗具有重要价值.     

血小板源性生长因子A在大鼠移植心脏血管病变及纤维化中的作用

目的 探讨血小板源性生长因子A(PDGF-A)在移植心脏血管病变及心肌纤维化中的作用.方法 选择近交系健康雄性Wistar大鼠及SD大鼠,建立大鼠异位心脏移植模型.实验分为四组,每组8只.正常对照组:取正常Wistar大鼠的心脏作为空白对照.无排斥组:心脏移植的供、受者均为Wistar大鼠,移植后第60天取移植心脏.急性排斥组和慢性排斥组:心脏移植的供者均为Wistar大鼠,受者均为SD大鼠;急性排斥组术后未行免疫抑制治疗,术后第5天取移植心脏;慢性排斥组术后给予环孢素A 10 mg·kg-1·d-1,皮下注射,移植后第60天取移植心脏.采用免疫组织化学染色法检测移植心脏的巨噬细胞浸润(CD68阳性细胞数)情况;逆转录聚合酶链反应(RT-PCR)分析PDGF-A mRNA的表达水平.结果 正常对照组和无排斥组未见巨噬细胞浸润;急性排斥组巨噬细胞浸润主要见于心肌及冠状血管周围;慢性排斥组巨噬细胞浸润见于心肌及血管周围,在心肌坏死纤维化较严重的区域,巨噬细胞浸润尤为明显;正常对照组、无排斥组、急性排斥组和慢性排斥组移植心组织中PDGF-A mRNA的相对表达量分别为:0.26±0.06、0.31±0.04、0.88±0.12和0.94±0.11,慢性排斥组和急性排斥组中PDGF-A mRNA的相对表达量明显高于正常对照组和无排斥组(P＜0.01).结论 巨噬细胞浸润及血小板源性生长因子表达水平与移植心脏血管病变及心肌纤维化有关.     

静脉注射免疫球蛋白治疗再次肾移植后加速性排斥反应一例

加速性排斥反应常可导致移植肾功能恢复延迟,甚至功能丧失.临床常用抗淋巴细胞球蛋白和静脉注射免疫球蛋白(IVIg)治疗,但疗效差异大.我们使用IVIg治疗再次肾移植后的加速性排斥反应1例,效果良好,现报道如下.临床资料患者为男性,52岁,1996年在我院行第1次肾移植.2008年3月开始,血肌酐逐渐升高,考虑为慢性排斥反应.2010年7月移植肾功能丧失,再次行血液透析.2010年11月在我院进行移植登记,其群体反应性抗体(PRA)阴性,患慢性丙型病毒性肝炎.     

慢性移植肾肾病的危险因素及发病机理

随着免疫抑制剂的不断研发,慢性移植肾肾病(chronic allograft nephropathy)已经取代急性排斥成为威胁移植物存活的主要病因.慢性移植肾肾病发病机理复杂,涉及免疫及非免疫因素,而强效免疫抑制剂的使用并不能明显降低慢性移植肾肾病的发生率.本文拟就慢性移植肾肾病的发病机理作一综述,以理清各种因素在慢性移植肾肾病的发病过程中的作用.     

NK细胞受体KIR在肾移植物排斥反应中的研究进展

器官移植的成功有赖于防止急性排斥反应的发生.细胞免疫和体液免疫两种机制参与移植排斥的理论已经成为共识,其中T细胞和B细胞分别作为介导排斥反应的细胞免疫和体液免疫的主要效应成分已经被广泛研究.NK细胞的自然杀伤功能在移植中的重要性随着对其实验研究成熟可行,也逐渐成为一个感兴趣的介导排斥反应物的研究领域,使学者们更加期望借此叮以解释和降低临床急性排斥的发生率.就NK细胞表面受休(immunoglobulin-like receptors)KIR和肾脏移植的研究进展,本文进行简要综述.     

肝移植术后慢性排斥反应的临床与病理分析

目的 探讨原位肝移植术后慢性排斥反应的病理组织学特点、临床表现以及诊治经验.方法 回顾性分析2004年1月至2006年12月收治的516例原位肝移植患者的临床病理资料;对肝移植术后发生慢性排斥反应患者的病理组织学改变、临床表现、诊治方案加以分析.结果 516例肝移植患者中,发生慢性排斥反应12例(2.3%,12/516),其中早期慢性排斥反应7例,晚期慢性排斥反应5例.其主要组织学特征是移植肝组织内的胆管严重减少或缺失和累及中等动脉的闭塞性动脉炎;其中早期慢性排斥反应可表现为小叶间胆管的细胞变性和其数量进行性减少以及形成小叶中央坏死性炎症.12例慢性排斥反应患者中,7例早期慢性排斥反应患者经激素冲击治疗和调整免疫抑制药物后病情得到控制(包括2例接受抗CD3抗体治疗,2例接受抗胸腺细胞球蛋白治疗)且近期疗效满意;5例晚期慢性排斥反应患者肝功能迁延不愈最终至肝功能衰竭而行再次肝移植,其中2例伴术后严重腹腔内感染而死亡,1例死于术后多脏器功能衰竭,另外2例再移植病例获临床治愈.本组慢性排斥反应发生的时间为术后4～26个月;与慢性排斥相关的病死率为25.0%(3/12).结论 肝移植术后发生慢性排斥反应的患者缺乏典型的症状和体征,其病理改变可以有重叠和复合存在;移植肝连续穿刺活检和再次移植术后病理仍是目前诊断慢性排斥反应的"金标准".如能及时发现早期慢性排斥反应并积极进行合理的治疗,病情则具有潜在的可逆性;晚期阶段慢性排斥反应所致的移植肝功能衰竭需要再次肝移植治疗.     

慢性移植肾病新进展

随着免疫抑制药物的发展，肾移植急性排斥反应基本上都可以得到控制，但慢性移植肾病(chronic allograft nephropathy)尚无明确有效的治疗药物和方法。慢性移植肾病既往被称为移植肾慢性排斥反应(chronic renal allograft rejection)，1992年第四次Alexis carrel移植器官慢性排斥反应和动脉硬化讨论会将肾移植慢性排斥反应定义为慢性移植肾病，它是导致移植。肾晚期功能丧失的最主要原因。本文就慢性移植肾病最新进展作一综述。     

Increased glomerular deposits of von Willebrand factor in chronic, but not acute, rejection of primate renal allografts

BACKGROUND: In our previously described primate renal allograft model, T cell ablation leads to long-term graft survival. The role of endothelial cell alteration in chronic rejection was examined in our model. METHODS: Renal transplants were performed in rhesus monkeys using a T cell- depleting immunotoxin, FN18-CRM9. Sections from 10 rejected kidneys (5 acute and 7 chronic rejection) were examined after immunohistochemical staining for expression of endothelium-related proteins [von Willebrand factor (vWF), CD62P, and CD31], fibrinogen, and a macrophage marker (CD68). Glomerular staining for each antigen was graded on a semiquantitative scale. RESULTS: Intense staining for vWF was consistently observed in glomerular endothelium, subendothelium, and mesangium in all kidneys removed due to chronic rejection. vWF staining was weak in kidneys showing acute rejection. The difference in glomerular staining was statistically significant. Staining for vWF in extraglomerular vessels was nearly identical in kidneys showing acute and chronic rejection. Expression of CD62P was increased in extraglomerular vessels in allografts with chronic rejection, but the glomeruli showed little or no staining. There was no significant difference in the glomerular staining for CD62P or CD31 in organs showing acute and chronic rejection. Fibrinogen staining of glomerular mesangium was seen in kidneys with chronic rejection. Macrophages (CD68+) infiltrating glomeruli were more numerous in kidneys showing chronic rejection. CONCLUSION: Increased glomerular deposition of vWF in renal allografts showing chronic rejection, without increased staining for CD62P or CD31, suggests increased constitutive secretion of vWF from endothelial cells as a component of the mechanism of chronic rejection in our model.     

Chronic rejection in primary renal allograft recipients under cyclosporine-prednisone immunosuppressive therapy

Although the introduction of cyclosporine-prednisone immunosuppression has improved early renal graft survival, chronic rejection remains a major cause of longterm graft dysfunction. This study retrospectively examined 69 cases of chronic rejection among 643 primary renal allograft recipients treated with cyclosporine-prednisone immunosuppression from July 1981 to October 1989. Chronic rejection was defined as a rejection episode diagnosed greater than 90 days posttransplantation with characteristics of progressive nonacute renal function deterioration, confirmed, in most cases, by renal biopsy. This group was compared with an equal-sized matched cohort. Among cadaveric recipients, 61 of 456 patients (13.4%) displayed chronic rejection, whereas among living-related recipients, 8 of 187 patients (4.3%) developed chronic rejection. The average time from the date of transplantation to diagnosis of chronic rejection was 15 +/- 14 months. One- and three-year graft survivals following diagnosis of chronic rejection were 51% (30/59) and 25% (13/51), respectively, compared with the cohort one- and three-year graft survivals of 98% (58/59) and 86% (32/37) at similar periods posttransplantation. HLA mismatch, PRA status, blood transfusion history, lipid levels, cyclosporine trough levels, incidence of prior acute rejection, and initial graft dysfunction were not significantly different between the chronic rejection group and the matched cohort. Hypertension and proteinuria were significantly associated with chronic rejection (P less than 0.001). Of 58 biopsies performed, findings solely consistent with chronic rejection were observed in 9 cases (15%) and "acute upon chronic" rejection in 49 cases (83%). Treatment of acute concomitants improved the renal function in 43% (27/63) by the time of hospital discharge. Nonetheless, at 12 months the incidence of improved renal function eroded to 22% (13/59), suggesting that the benefit was relatively short-lived. Although the overall incidence of chronic rejection in this group of cyclosporine-prednisone-treated patients was lower than previous azathioprine-prednisone cohorts, the clinical presentation and progression of chronic rejection was similar. Additionally, the incidence of chronic rejection within this series was lower among living-related recipients versus cadaveric recipients of donor organs.     

内皮素在移植肾急性或慢性排斥反应中的变化

目的：探讨内皮素—1(ET—1)在移植肾急性或慢性排斥反应(简称急排或慢排)中的变化。方法：对43例肾移植术1年后患者(对照组18例，急排组9例，慢排组16例)行血液、尿液ET—1、肌酐、β2—M排泄量等测定，对部分急排和慢排移植肾行ET—1及A受体免疫组织化学染色。结果：急排组血、尿ET—1高于对照组(P＜0．01)；急排组尿ET—1明显高于慢排组(P＜0．01)，两组间血ET—1的差异无明显意义(P＞0．05)；急排和慢排时血ET—1均与血肌酐呈正相关(P＜0.01)，尿ET—1均与尿β2—M排泄量呈正相关(P＜0．01)；免疫组织化学染色显示ET—1与ETA受体在移植肾内的分布较一致，与相应病理类型大致吻合，急排和慢排检测时，其染色强度明显高于正常肾脏。结论：检测尿ET—1排泄量可鉴别急排和慢排，术后监测尿ET—1较监测血ET—1更有意义；在急排和慢排中ET系统可能担当重要角色。     

Risk factors for chronic rejection after pediatric liver transplantation

BACKGROUND: Chronic rejection is a major cause of graft failure and a frequent reason for retransplantation after pediatric liver transplantation. Identification of risk factors for chronic rejection in pediatric transplant recipients is vital to understanding the pathogenesis of chronic rejection and may help prevent further graft loss. METHODS: The study population consisted of 285 children with 385 liver transplants performed at University of Chicago between 1991 and 1999. Logistic regression analysis was used to evaluate risk factors for chronic rejection, including age, sex, race, type of graft (living related vs. cadaveric), native liver disease, acute rejection episodes, cytomegalovirus (CMV) infection, and posttransplant lymphoproliferative disease (PTLD). RESULTS: The chronic rejection rate was significantly lower in recipients of living-related grafts than in recipients of cadaveric grafts (4% vs. 16%, P=0.001). African-American recipients had a significantly higher rate of chronic rejection than did Caucasian recipients (26% vs. 8%, P<0.001). Numbers of acute rejection episodes, transplantation for autoimmune disease, occurrence of PTLD, and CMV infection were also significant risk factors for chronic rejection. However, recipient age, gender, donor-recipient gender mismatch, and donor-recipient ethnicity mismatch were not associated with higher incidence of chronic rejection CONCLUSION: We have identified a number of risk factors for chronic rejection in a large group of pediatric liver allograft recipients. We believe that donor-recipient matching for gender or race is not likely to reduce the incidence of chronic rejection. The elucidation of the mechanisms by which living-related liver transplantation affords protection against chronic rejection may provide insight into the immunogenetics of chronic rejection and help prevent further graft loss.     

Predominant expression of the Th2 response in chronic cardiac allograft rejection

Chronic rejection is the main cause of late allograft failure in patients. CD4+ T cells activated by indirect recognition of alloantigens are implicated in this rejection reaction. However, the type of T cell response (Th1 vs Th2) that contributes to chronic rejection has not been fully investigated. The purpose of this study is to examine whether chronic rejection is associated with a polarized T-cell response in a rat cardiac allograft model, where long-term graft survival is achieved by intrathymic immunomodulation with donor class I, RT1.Aa, allopeptides. All long-surviving allografts showed histological evidence of chronic rejection. Chronic rejection was associated with high levels of intragraft Th2 cytokines and the Th2-regulated alloantibodies. The Th2 response was systemic, since long-surviving allografts with chronic rejection had high levels of serum IL-10. The predominance of the Th2 cytokines demonstrates that the Th2 response was not sufficient for the prevention of chronic rejection in this model. The predominant expression of Th2 cytokines, together with the presence of Th2-regulated alloantibodies, suggests that the Th2 response may play a role in the development of chronic rejection.     

肾移植排斥反应患者血清蛋白质谱的差异性研究

目的 研究肾移植排斥反应患者的血清蛋白质谱的差异性,检测肾移植排斥反应早期诊断的特殊血清多肽标记物.方法 将研究对象分成实验组和对照组,实验组为经肾活检确诊的10例急性排斥反应和12例慢性排斥反应患者,对照组为12例移植肾功能稳定受者和13例健康志愿者.通过ClinProt磁珠浓缩和基质辅助激光解吸电离法(MALDI)-TOF-MS分析两组研究对象的血清蛋白质谱的差异.结果 通过与健康对照组比较,筛选出18条差异性多肽作为诊断肾移植急性排斥反应的潜在生物标记物,6条差异性多肽作为诊断慢性排斥反应的潜在生物标记物.此外,还比较了急性排斥反应与慢性排斥反应患者的多肽差异,检测出了4条高表达的差异性多肽.运用快速分类算法,建立了移植排斥反应的分类模型,该模型对急性排斥反应患者的有效识别能力达到82.64%,对慢性排斥反应患者的有效识别能力高达98.96%.结论 基于功能性磁珠的样本分离法结合MALDI-TOF-MS分析的实验方法 是精确而稳定的.应用蛋白质组学技术建立了肾移植排斥反应患者的血清蛋白质谱诊断模型,为人们更好的理解肾移植排斥反应的发病机制,并将蛋白质组学技术用于排斥反应早期诊断的新技术手段提供了思路.     

Chronic rejection of mouse kidney allografts

BACKGROUND: Chronic renal allograft rejection is the leading cause of late graft failure. However, its pathogenesis has not been defined. METHODS: To explore the pathogenesis of chronic rejection, we studied a mouse model of kidney transplantation and examined the effects of altering the expression of donor major histocompatibility complex (MHC) antigens on the development of chronic rejection. RESULTS: We found that long-surviving mouse kidney allografts develop pathological abnormalities that resemble chronic rejection in humans. Furthermore, the absence of MHC class I or class II antigens did not prevent the loss of graft function nor alter the pathological characteristics of chronic rejection. Expression of transforming growth factor-beta (TGF-beta), a pleiotropic cytokine suggested to play a role in chronic rejection, was markedly enhanced in control allografts compared with isografts. However, TGF-beta up-regulation was significantly blunted in MHC-deficient grafts. Nonetheless, these differences in TGF-beta expression did not affect the character of chronic rejection, including intrarenal accumulation of collagens. CONCLUSIONS: Reduced expression of either class I or II direct allorecognition pathways is insufficient to prevent the development of chronic rejection, despite a reduction in the levels of TGF-beta expressed in the allograft. This suggests that the severity of chronic rejection is independent of the level of MHC disparity between donor and recipient and the level of TGF-beta expression within the allograft.     

Pathogenesis of chronic renal allograft dysfunction

The pathogenesis of chronic renal allograft dysfunction was reviewed. Chronic rejection/chronic renal allograft nephropathy is the most prevalent cause of renal graft loss after the first year post-transplant. Both immunologic and non-immunologic factors play key roles in the pathogenesis of chronic allograft nephropathy. Acute rejection episodes are the most prevalent risk factor for chronic rejection. Many risk factors for chronic allograft nephropathy have been identified, such as glomerular hyper-filtration, delayed graft function, repeated acute rejection, systemic hypertension and hyperlipidemia. However, the precise pathogenesis of chronic allograft nephropathy remains obscure. The differential diagnosis of immunologically mediated chronic rejection and chronic allograft dysfunction caused by non-immunologic factors is usually impossible using clinical parameters. The histopathologic findings of chronic allograft nephropathy are progressive interstitial fibrosis with tubular atrophy and thickening of vascular intima, and these findings are non-specific. Therefore, the term chronic allograft nephropathy may be clinically preferable to chronic rejection to describe the gradual decline in graft function. The most effective way to prevent chronic allograft dysfunction is to avoid any kind of graft damage via immunologic or non-immunologic pathway.