【作者】 刘刚；

【导师】 赵明；

【作者基本信息】 南方医科大学 ， 临床医学（专业学位）， 2013， 博士

【摘要】 背景肾移植是治疗慢性肾衰竭患者的最理想疗法。肾移植的历史从某种意义来说就是同排斥反应进行斗争的历史。肾移植后的排斥反应主要是由抗原识别,淋巴细胞的增殖、分化,靶细胞的损伤这样一连串的免疫反应引起的。随着新型免疫抑制剂的应用,急性排斥反应的发生率明显下降,但临床上急性排斥反应造成的慢性移植肾肾病的风险反而越来越高。美国资料显示急性排斥反应的发生率虽然下降,但是针对排斥反应的抗体治疗的比例反而明显增加,提示肾移植后急性排斥反应仍然是临床中的一个大问题。浙江大学医学院附属第一医院肾脏病中心1200例次肾移植急性排斥反应的发生情况,发现急性排斥反应的发生明显影响肾移植受者长期预后,发生多次排斥反应者预后更差,晚期(移植6个月以后)发生排斥反应者较早期发生排斥反应者预后更差,慢性移植肾失功发生率较高。急性排斥反应是否完全逆转也明显影响肾移植受者预后,其中未完全逆转的患者慢性移植肾失功发生率更高。急性排斥反应是影响移植肾存活的重要因素,发生率为20%-50%。急性排斥反应不仅会增加移植肾早期失功及其他并发症的发生率和相关治疗费用,而且是导致后期移植肾丢失的一个重要的独立危险因素。预防和减少早期急性排斥反应的发生有利于移植受者和移植物的长期存活。Alemtuzumab主要作用的靶细胞是T淋巴细胞。Alemtuzumab最初用于治疗慢性淋巴细胞白血病,此后又用于治疗多发性硬化、类风湿性关节炎、血管炎等自身免疫性疾病。近年Alemtuzumab应用于实体器官移植。美国OPTN/SRTR(Organ Procurement and Trans-plantation Network and the Scientific Registry of Transplant Recipients)年度报告表明,自2003年至2006年Alemtuzumab在实体器官移植中的应用呈逐年上升趋势,2006年在各种实体器官移植受者中使用Alemtuzumab所占比例为：小肠移植21.4%、胰腺移植13.4%、肾移植10%、肺移植7.2%、心脏移植1.7%、肝移植1.4%。自1998年Calne等[2]首次报道Alemtuzumab诱导治疗用于肾移植后,Alemtuzumab诱导治疗在器官移植领域逐步引起广泛关注。Alemtuzumab是一种人源化的鼠抗CD52单克隆IgG1抗体免疫抑制剂。CD52是细胞膜表面小分子糖蛋白,广泛表达于T淋巴细胞、B淋巴细胞、自然杀伤细胞、单核细胞等免疫细胞膜表面。Alemtuzumab的作用是迅速清除移植物受体外周血T淋巴细胞和B淋巴细胞,使得受体虽然可以识别供体抗原但只能发生免疫应答,而不能发生排斥反应。最终,Alemtuzumab通过选择性清除对供体抗原有免疫应答的T淋巴细胞和B淋巴细胞克隆,使受体产生对移植物的免疫耐受。最近的研究表明,Alemtuzumab在诱导免疫耐受方面可能还有其他重要作用机制。’肾移植受者使用Alemtuzumab后外周血CD4+CD25+FOXP3+调节性T细胞[5]和记忆性T细胞增生。调节性T细胞增生有利于诱导和维持移植免疫耐受,CD28-CD8+记忆性T细胞增生竞争性抑制CD4+T细胞,延缓CD4+T细胞介导的细胞免疫恢复。研究还发现肾移植受者使用Alemtuzumab后外周血树突状细胞减少,髓样树突状细胞/浆细胞样树突状细胞比例降低。树突状细胞作为抗原递呈细胞诱导移植后T细胞免疫反应,髓样树突状细胞介导T细胞向Th1分化,浆细胞样T树突状细胞介导T细胞向Th2分化。因此Alemtuzumab可能通过抑制树突状细胞介导的T细胞向Th1分化和促进树突状细胞介导的T细胞向Th2分化的途径调节获得性免疫耐受。在临床肾移植应用中,Alemtuzumab常可与环孢素、FK506、皮质类固醇激素、硫唑嘌呤或MMF联合使用[8],以达到满意的免疫抑制效果。目的探讨人源化的鼠抗CD52单克隆IgG1抗体----Alemtuzumab(阿伦单抗)对移植肾急性排斥反应的预防作用、移植物及受者存活率的影响。方法本文主要遵循随机对照试验meta分析的相关指南进行资料收集及分析,收集国内外关于Alemtuzumab用于预防移植肾急性排斥反应的随机对照试验,时间自1998年1月至2012年5月之间,文献纳入标准为：(1)、随机对照试验,可采用随机数字表、计算机随机排列、抛硬币法、抽签法等；(2)、试验纳入同一时期平行的对照组；(3)、试验组与对照组除Alemtuzumab外其余干预措施相同。采用Jadad文献研究质量评分标准对纳入文献进行质量评价。采用固定效应模型,RR值为效应指标的相关研究。I1指数行异质性检验,并行敏感性分析观察单个临床试验研究对总体分析结果的影响。按照研究随访时间长短(半年内、1年内、2年内)、移植物存活率、受者存活率行分析并探索可能存在的异质性来源。采用Revman5.1软件进行数据处理与分析。计数资料采用M-H法,选用风险比(RR),两者均计算95%可信区间(95%CI)。所有统计学指标均为双侧,P<0.05认为差异有统计学意义。结果共收集国内外9个随机对照试验,其中国内1篇,国外8篇。Meta分析结果显示：Alemtuzumab对预防移植肾急性排斥反应优于空白对照组。其中半年的Meta分析结果(RR=0.42,95%CI(0.29,0.62,P<0.01),即应用Alemtuzumab组术后半年的排斥反应发生率比空白对照组低55%；1年的Meta分析结果(RR=0.49,95%CI(0.35,0.69),P<0.01),即应用Alemtuzumab组术后1年的排斥反应发生率比空白对照组低51%；2年的Meta分析结果(RR=0.73,95%CI(0.53,1.02),P=0.06),即应用Alemtuzumab组术后2年的排斥反应发生率与空白对照组无明显差异；对移植物存活率影响的Meta分析结果(RR=1.01,95%CI(0.98,1.05),P=0.47),对受者存活率影响的Meta分析结果(RR=1.00,95%CI(0.97,1.02),P=0.85),即应用Alemtuzumab组术后对移植物及受者存活的影响与空白对照组比较无明显差异。结论Alemtuzumab对移植肾急性排斥反应具有明显的预防作用,但对移植物及受者存活无影响。更多还原

【Abstract】 BackgroundRenal transplantation is the most ideal therapy in patients with chronic renal failure. the History of renal transplantation in a sense is locked in battle with rejection of history. Rejection after renal transplantation is mainly composed of antigen recognition, lymphocyte proliferation, differentiation, target cells damage so caused a series of immune reaction. With the use of new immunosuppressant, the incidence of acute rejection decreased obviously, But clinical acute rejection caused by the risk of chronic renal allograft nephropathy is higher and higher. The data show that although the incidence of acute rejection to fall,But in view of the rejection of the antibody treatment increased significantly, the proportion of the; prompt Hint of acute rejection after kidney transplantation is still a big problem in clinical; The first hospital affiliated to zhejiang university school of medicine center,1200cases of kidney disease occurrence of acute rejection in renal transplant recipients;Found that significantly influence the occurrence of acute rejection in kidney transplant recipients long-term prognosis, Prognosis is worse happens many times rejection, After6months) late (transplantation rejection reactions in earlier for the poorer prognosis, high incidence of chronic renal allograft loss. Acute rejection is whether it is totally reversed significantly affect the prognosis of renal transplant recipients, which have not completely reversed in patients with chronic renal allograft loss after higher..Acute rejection is the important factors that affect graft survival and incidence ranged from20%to50%;Acute rejection will not only increase the incidence of early renal allograft loss and other complications and related cost of treatment, and it is the leading cause of late graft loss is an important independent risk factors. To prevent and reduce the occurrence of early acute rejection for transplant recipients and the long-term graft survival. Alemtuzumab is the main target cells in a role of T lymphocytes.Alemtuzumab originally used in the treatment of chronic lymphocytic leukemia, then used in the treatment of multiple sclerosis, autoimmune diseases such as rheumatoid arthritis, vasculitis. In recent years, Alemtuzumab is applied to solid organ transplantation, America’s annual report shows:From2003to2003Alemtuzumab in solid organ transplantation, there is an upward trend in the application.In2006in various kinds of solid organ transplant recipients with Alemtuzumab proportion is:small intestine transplantation21.4%21.4%13.4%, pancreas transplantation, renal transplantation, lung transplantation, heart transplantation, liver transplantation,1.7%and1.4%7.2%. Calne, etc for the first time since1998, reported Alemtuzumab induction of immune tolerance after treatment for a kidney transplant, Alemtuzumab induction of immune tolerance treatment gradually caused widespread concern in the field of organ transplantation.Alemtuzumab is a kind of humanized mice CD52monoclonal IgG1antibody immune inhibitors. CD52small molecules on the cell membrane surface glycoprotein, is widely expressed on T lymphocytes and B lymphocytes, natural killer cells, mononuclear cells such as immune cell membrane surface. Alemtuzumab is quickly remove graft receptors on peripheral blood T lymphocytes and B lymphocytes, although make the receptor can identify the donor antigen immune response but can only occur, rather than rejection. Eventually, Alemtuzumab through selective removal of donor antigen immune response of T lymphocyte and B lymphocyte clones, the receptors of graft immune tolerance Recent studies have shown that Alemtuzumab there may be other important role in the induction of immune tolerance mechanism. Kidney transplant recipients with alemtuzumab after peripheral blood CD4+CD25+FOXP3+regulatory T cells in5and memory T cells proliferation. Regulatory T cell proliferation is advantageous to the induction and maintenance of transplantation tolerance and CD28-CD8+memory T cells proliferation competitive inhibition of CD4+T cells and delay the cells of CD4+T cell mediated immune recovery. The study also found that after kidney transplant recipients who use alemtuzumab peripheral blood dendritic cells decreased, myeloid dendritic cells7sample/plasma cells, dendritic cells proportion decreased. Dendritic cells as antigen presented the induction of T cell immune response after transplantation, myeloid dendritic cells mediated by T cells to Thl differentiation, plasma cells, T dendritic cells mediated by T cell to Th2differentiation. Therefore Alemtuzumab may be mediated by inhibition of dendritic cells to Thl differentiation of T cells and dendritic cells mediated by T cell to Th2differentiation pathway regulating acquired immune tolerance.In clinical renal transplantation application, Alemtuzumab often with cyclosporina, FK506, corticosteroids, azathioprine, or mycophenolate mofetil combined, in order to achieve satisfactory result of immunosuppression.ObjectiveTo study the effect of Alemtuzumab, a humanized CD52monoclonal antibody, on the prevention of acute rejection and promoting graft and patient survival in renal allograft recipients.MethodsThis experment follows a meta analysis of randomized controlled experiment related guide to collection and analysis data, collect the data of randomized controlled trials obout the effect of Alemtuzumab on renal graft rejection and survival,since January1998to May2012,the standard of the data include:1. randomized controlled trial;2.experiments in the same period of the control group;3.the same intervention measures.we use the Jadad literature research and the quality criteria to evaluation the quality of the data.Random effects meta-analysis and relative risk were used to estimate.Heterogeneity was assessed using the Cochran’s Q test and the Higgins I-squared statistic (I2),Sensitivity analyses were carried out to characterize possible sources of statistical heterogeneity, by excluding studies one-by-one.group analyses based on duration of follow-up, renal graft and patient survival,were conducted to identify the risk-subgroup interactions that could explain the inter-study differences. The statistical analyses were performed with RevMan5.1software. statistics data using M-H method, the risk ratio (RR).All the p values were two tailed, and p values<0.05were considered statistically significantResultsA total of9pertinent research articles were reviewed, including1paperswritten by Chinese authors and8by foreign authors. Meta-analysis of pooled results indicated that Alemtuzumab prevented the recipients of kidney transplantation from acute rejection effectively with half year prevention of RR0.42and95%CI0.29-0.62(P<0.01), and one year prevention of RR0.49,95%CI0.35-0.69(P<0.01), and two year prevention of RR0.73,95%CI0.53-1.02(P=0.06). It was revealed that Alemtuzumab could reduce the incidence of acute rejection by55%in half year,51%in one year and28%in two year. No statistical difference of graft and patient survival was found between Alemtuzumab and control group (RR=1.01,95%CI (0.98,1.05), P=0.47and RR=1.00,,95%CI(0.97,1.02), P=0.85), implying that Alemtuzumab did not throw an influence on graft and patient survival.ConclusionsAlemtuzumab may effectively prevent the recipients of kidney transplantation from acute rejection. No statistical difference of graft and patient survival exists between the patients receiving Alemtuzumab treatment and control group.更多还原