T淋巴细胞与肝移植免疫耐受

背景：肝移植排斥反应的发病机制主要是T细胞介导的免疫应答,具有调节细胞功能的高活性、多功能的低分子蛋白质即细胞因子在器官移植排斥反应和免疫耐受中发挥着重要作用。目的：就T淋巴细胞与肝移植后免疫耐受的关系及研究现状作一综述。方法：由第一作者检索Medline 数据库及维普医学数据库1995年1月至2013年6月有关肝移植后免疫状态与T淋巴细胞及其细胞因子作用的文献。以“liver transplantation, immune tolerance, rejection, T lymphocytes”为英文检索词,“肝移植,排斥反应,免疫耐受,T淋巴细胞”为中文检索词,排除重复研究类文章。选取相关文献查找全文,纳入57篇,其中有关T淋巴细胞与移植后免疫状态研究背景的文献9篇,有关调节性T细胞在移植免疫中的作用10篇,有关T淋巴细胞与移植后免疫耐受关系的文献17篇,有关T淋巴细胞与移植后免疫耐受研究前景的文献21篇。结果与结论：T淋巴细胞是调节机体免疫应答一类重要的免疫细胞。接受同种异体肝移植后,受体发生免疫排斥还是免疫耐受与免疫系统中T淋巴细胞的亚群及其功能密切相关。通过阻断或诱导T淋巴细胞的某些功能可以诱导宿主免疫耐受。 中国组织工程研究杂志出版内容重点：肾移植;肝移植;移植;心脏移植;组织移植;皮肤移植;皮瓣移植;血管移植;器官移植;组织工程全文链接：     

肾移植后急性排斥反应及免疫抑制剂的应

背景：肾移植后急性排斥反应在临床较为常见,免疫抑制剂的出现促进和推动了肾移植质量的提高,免疫抑制剂的合理应用对肾移植患者至关重要,成为影响患者生存率的重要因素。 目的：对肾移植后急性排斥反应和免疫抑制剂研究文献进行多层次分析。 方法：以电子检索方式对Web of Science数据库2002至2011年收录肾移植后急性排斥反应和免疫抑制剂研究的文献进行分析,采用检索词为“肾移植;急性排斥反应;免疫抑制剂”。对肾移植后排斥反应进行分类,了解肾移植后免疫抑制剂的种类,分析各种免疫抑制剂的特点。 结果与结论：Web of Science数据库2002至2011年收录肾移植后急性排斥反应和免疫抑制剂研究的文献共6 105篇,文献数量总体呈现出逐步上升的发展状态,《移植学会会报》杂志是发表肾移植后急性排斥反应和免疫抑制剂研究文献较多的期刊。美国在此类研究中发表文献最多,其次为德国。收录文献按被引频次由高到低排序前10位中,有4篇来源于《新英格兰医学》杂志。中国在过去10年间被收录文章总量排在第9名,共发表238篇相关文献,中国的国家自然科学基金资助文献有17篇。     

HLA抗体筛选技术的最新进展及其在器官移植中的应用

人类白细胞抗原(HLA)是介导器官移植排斥反应的主要因素,良好的组织配型是肾移植患者长期存活和术后移植肾功能恢复的重要条件之一。在多次输血、生育史、再次移植的受者受到同种HLA免疫致敏可产生群体反应性抗体(panelreactive antibody,PRA)。PRA是一组特定的人类白细胞抗原(HLA)抗体,有多种类型,包括HLA-A、B、C、DR、DQ等抗体[1],是造成超急性和加速性排斥反应和移植物丢失的危险因素之一。PRA水平的高低更直接地影响移植肾的近期存活率。因此,将抗体筛选技术应用于器官移植实践,对减少移植后排斥反应,提高移植成功率和移植…     

免疫抑制药物在抗移植排斥反应过程中的应用

背景：器官移植患者需要终生伴随免疫抑制剂,因此合理应用免疫抑制剂是器官移植成功的关键所在。 目的：对各类代表药物在器官移植中的应用作简要分析,拟为器官移植患者选择合适的免疫抑制剂。 方法：由第一作者检索1999-01/2011-06 PubMed数据库(http://www.ncbi.nlm.nih.gov/PubMed)和万方数据库(http://www.wanfangdata.com.cn)。英文检索词为“immunosuppressive drug;reject reaction;cyclosporine A;tacrolimus(FK506)”,中文检索词为“免疫抑制剂,肾移植,肝移植,排斥反应”。检索文献量总计105篇,选择不同种类的免疫抑制药物在不同器官移植领域应用的特点及临床效果分析,排除陈旧及重复实验文章,同一领域文献则选择近期发表或发表在权威杂志的文章,最终纳入18篇符合标准的文献。 结果与结论：常见免疫抑制药分类：肾上腺皮质激素、代谢拮抗药、T淋巴细胞抑制药。然而每一种免疫抑制剂在发挥免疫抑制作用时都会伴有一定毒副反应,应尽量避免不良反应发生。如何利用免疫抑制药之间的协同作用,发挥最佳疗效是临床需进一步关注和研究的重点,应严密监测患者血药浓度,做到个体化用药,尽可能降低毒副反应发生率。     

肾移植后不同免疫抑制剂抗排斥反应的临床应用及不良反应

背景：如何利用免疫抑制剂之间的协同作用,发挥最佳疗效是肾移植后抗排斥反应的关键所在,如何做到个体化用药,提高疗效避免不良反应的发生显得尤为重要。 目的：评价不同免疫抑制剂对肾移植受者和移植肾存活的影响,以便更好地避免药物不良反应。 方法：应用计算机检索1999-01/2009-10 CNKI数据库相关文献,检索词为“免疫抑制剂,肾移植,排斥反应”。选择文章内容与肾移植免疫抑制剂有关者,同一领域文献则选择近期发表或发表在权威杂志文章,入选25篇文献进行综述。 结果与结论：任何一种免疫抑制剂在发挥免疫抑制作用时都会伴有一定毒副作用,临床上应尽量避免不良反应发生。联合用药抗排斥反应已达成共识,事实证明无论采用何种联合方式,均有单一用药无可替代的优势。如何利用免疫抑制药之间的协同作用,发挥最佳疗效是临床关键所在,医生应严密监测患者血药浓度,做到个体化用药,尽可能降低肾移植后排斥反应发生率。关键词：免疫抑制剂;肾移植;排斥反应;环孢素A;吗替麦考酚酯;他克莫司 doi:10.3969/j.issn.1673-8225.2012.18.032      

群体反应性抗体与器官移植

群体反应性抗体(PRA)是移植中最重要的免疫因素。研究证明移植排斥是由体液免疫介导的,PRA分析能反映受者人类白细胞抗原(HLA)的致敏状态,在移植前预测排斥反应的发生和移植后预警移植物丧失,使器官移植后各种排斥反应的发生率显著降低。目前PRA尤其是特异性抗供者抗体(DSA)在肾、心脏、肺等实体器官移植中的作用及其前瞻性应用研究成为热点。本文就PRA与器官移植的研究进展进行综述。     

异种肌腱移植免疫反应的处理方法

背景：异体肌腱移植是目前修复肌腱缺损的理想方法。其中异种肌腱供源丰富,但移植后的排斥反应为其使用受到限制的主要原因。 目的：对异种肌腱的抗原性和移植后的免疫反应及降低异种肌腱排斥反应的方法的研究进展进行综述。 方法：第一作者应用计算机检索PubMed数据库和CNKI数据库中1995-01/2010-12在标题和摘要中以“肌腱,异体移植,免疫”或“tendons,transplantation Immunity,”为检索词进行检索。选择文章内容与肌腱移植免疫反应相关,同一领域文献则选择近期发表或发表在权威杂志文章。初检得到196篇文献,根据纳入标准选择30篇文章进行综述。 结果与结论：目前对异种移植物抗原的研究包括半乳糖-a-1,3-半乳糖抗原(Gal)和非Gal抗原,以对Gal抗原基因研究的较多。Gal抗原由存在于哺乳动物细胞表面的Gal-a-1,3-Gal抗原引起,是引起超级排斥反应的主要因素。异种肌腱移植后早期以细胞免疫为主,晚期仅有体液免疫参与;动物实验表明经不同物理和化学方法处理后的异种肌腱有潜在应用价值。肌腱移植不同于器官移植,肌腱移植属于非功能性移植,异体肌腱只为受区提供一个生长支架,移植后的生物学特点主要体现在生物力学上,因此,探讨出新的消除免疫原性同时保留移植物生物力学特性的方法是异种肌腱移植获得突破的关键。     

中国肝移植后排斥反应研究的发展趋势

背景：终末期肝病患者可以通过移植全部肝脏或部分肝脏来挽救生命,随着新型免疫抑制药物的出现,肝移植后排斥反应的发生率大幅度降低,使患者的生存率得到明显提高。 目的：对肝移植后排斥反应研究的文献资料趋势进行多层次探讨分析。 方法：以电子检索方式对CNKI数据库学术期刊和博士学位论文数据库2002-01/2011-12收录有关肝移植后排斥反应研究的文献进行分析,采用检索词为“肝移植;排斥反应”,应用数据库的分析功能和Excel软件图表的功能分析数据特征。 结果与结论：在CNKI数据库学术期刊2002/2011收录的文献中,共检索到777篇与肝移植后排斥反应研究相关的文献,从文献数量上看,2006年的文献数量处于顶峰为110篇,2007年《人体器官移植条例》颁布以前处于上升趋势,到2007年开始略有下降。文献的基金资助项目数量比较多,39个基金资助项目文献共有210篇,省级基金资助项目数量为28个,其中广东省的基金项目最多为4个。《中华器官移植杂志》是中国肝移植后排斥反应研究的权威期刊。肝移植后排斥反应的研究主要以大鼠的动物实验为主,移植后急性排斥反应的发生率比较高,强效的新型免疫抑制剂以他克莫司的研究较多。在博士学位论文数据库中检索到90篇相关文献,文献数量、学科类别、研究机构、关键词和基金资助项目结果与CNKI数据库学术期刊文献结果基本相似。     

同种异体肌腱移植修复运动损伤：免疫排斥反应及降低免疫排斥反应的方法

背景：异体肌腱来源丰富,取材方便,既保持原有的生物结构特性,又能满足供体质与量的要求。但是,未经处理的异体肌腱移植后免疫排斥反应较大。 目的：评价同种异体肌腱移植修复损伤的效果,总结降低免疫排斥反应的方法。 方法：采用电子检索的方式,在万方数据库(http://www.wanfangdata.com.cn/)中检索1990-01/2011-11关于同种异体肌腱移植修复损伤的免疫排斥反应及降低免疫排斥反应方法研究的文章,关键词为“同种异体,肌腱,重建”。排除重复研究、普通综述或Meta分析类文章,筛选纳入33篇文献进行评价。 结果与结论：同种异体肌腱移植最主要的问题是组织相容性较差,免疫排斥强烈。未经过处理的同种异体肌腱修复损伤后,植入的肌腱会出现坏死、免疫排斥反应等不良现象使移植失败率较高。降低免疫排斥反应的方法主要有：低温冷冻异体肌腱、冷冻干燥异体肌腱、药物浸泡肌腱、射线灭菌法保存肌腱。提示同种异体肌腱移植免疫排斥反应是临床应用中最为棘手的问题,但低温冷冻异体肌腱等方法的应用很好地解决了这一问题,并在临床应用中发挥出很好的效果。     

CD4~+CD25~+调节性T细胞在同种异体移植免疫耐受中的研究进展

同种异体器官移植已经成为终末器官衰竭患者修复病损的组织和器官,并重建其功能必要的治疗方法。受者往往都需要长期接受免疫抑制剂来维持移植物在其体内的存活。由于免疫抑制剂的非特异性及毒副作用,长期应用该类药物会导致受者免疫力低下而出现易感染、癌症等副作用。因此,解决该问题的关键是诱导受者对供者移植抗原产生特异性地"移植免疫耐受"。大量研究结果显示,CD4+CD25+调节性T细胞能特异性地抑制免疫排斥反应,在调控免疫应答与维持外周免疫耐受中发挥着重要作用。本文对近年来CD4+CD25+调节性T细胞的作用机制及其在同种异体移植免疫耐受方面的研究进行了综述。     

蛋白质组学在肾移植急性排斥反应标志物筛选中的应用进展

尽管肾移植是治疗终末期肾病的最佳选择, 但是移植后的免疫排斥仍然是困扰临床的重大难题, 急性排斥反应是最常见的移植后免疫排斥反应。 移植医学在预防性筛查、 早期诊断、 改善预后和治疗等方 面正面临着新的特异性生物标记物的需求。 目前, 蛋白质组学的已经被广泛应用于移植医学的研究中, 血 清、 尿液中与肾移植后急性排斥反应相关生物标志物的筛选也取得越来越多的进展。 文章综述了基于质谱 技术的蛋白组学在肾移植后急性排斥反应相关的生物标志物筛选中的研究进展。     

恒河猴肝移植急性排斥反应中核因子κB p65的表达

背景：核因子κB作为一种重要的核内转录因子,是多种信号转导途径的汇聚点,参与机体免疫细胞的增殖、分化及细胞凋亡等多种反应物质基因的表达调控,在体液和细胞免疫中发挥重要作用。 目的：探讨恒河猴移植肝组织内核因子κB P65蛋白表达与急性排斥反应的关系。 方法：将恒河猴随机分为2组：急性排斥反应组肝移植后不给予抗排斥处理,对照组肝移植过程中及移植后均给予抗排斥处理。分别在移植后6,12,24和72 h 4个时间点收集血标本,全自动生化分析仪测定丙氨酸氨基转移酶、总胆红素,取移植肝脏组织行苏木精-伊红染色观察组织形态结构和排斥反应,根据Banff评分系统判断排斥反应程度,采用Western blot法检测肝脏组织中核因子κB p65的表达。 结果与结论：肝移植急性排斥反应发生时肝功能变化滞后于肝组织病理学检查。当急性排斥反应发生时,移植肝组织中核因子κB p65表达上调,急性排斥反应程度也随之加剧。并且在急性排斥反应早期,肝功能、病理学仅有轻微改变时,核因子κB p65表达显著升高。因此移植肝组织中核因子κB p65表达水平的检测对移植后急性排斥反应的早期诊断有重要意义,同时核因子κB可能成为控制移植急性排斥反应的新靶点。     

Role of antibodies to self-antigens in chronic allograft rejection: Potential mechanism and therapeutic implications

Significant progress has been made in preventing acute allograft rejection following solid organ transplantation resulting in improved allograft survival. However, long term function still remains disappointing primarily due to chronic allograft rejection. Alloimmune responses primarily defined by the development of antibodies (Abs) to donor mismatched major histocompatibility antigens during the post-transplantation period have been strongly correlated to the development of chronic rejection. In addition, recent studies have demonstrated an important role for autoimmunity including the development of Abs to organ specific self-antigens in the pathogenesis of chronic allograft rejection. Based on this, a new paradigm has evolved indicating a possible cross-talk between the alloimmune responses and autoimmunity leading to chronic rejection. In this review, we will discuss the emerging concept for the role of cellular and humoral immune responses to self-antigens in the immunopathogenesis of chronic allograft rejection which has the potential to develop new strategies for the prevention and/or treatment of chronic rejection.     

CMV driven CD8 T-cell activation is associated with acute rejection in lung transplantation

Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8⁺ T-cell activity post-transplant. Peripheral and lung CMV-specific CD8⁺ T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8⁺ T-cells in the lung may play a role in promoting acute rejection.     

CD4+ T-cell-dependent tumour rejection in an immune-privileged environment requires macrophages

Although intraocular tumours reside in an immune-privileged site, they can circumvent immune privilege and undergo rejection. Ocular tumour rejection typically follows one of two pathways. One pathway involves CD4+ T cells, delayed-type hypersensitivity (DTH), and culmination in ischemic necrosis of the tumour and phthisis (atrophy) of the eye. The second pathway is DTH-independent and does not inflict collateral injury to ocular tissues, and the eye is preserved. In this study, we used a well-characterized tumour, Ad5E1, to investigate the role of CD4+ T cells in the non-phthisical form of intraocular tumour rejection. It has been previously documented that CD4+ T cells and interferon (IFN)-gamma are necessary for rejection of these tumours in the eye. In this study, we demonstrate that CD4+ T cells can circumvent immune privilege and infiltrate intraocular Ad5E1 tumours. Following tumour rejection, CD4+ T cells from tumour rejector mice could be adoptively transferred to severe combined immunodeficiency (SCID) mice and protect them from intraocular Ad5E1 tumour growth. Tumour-specific CD4+ T cells produced IFN-gamma in response to Ad5E1 tumour antigens. Macrophages also contributed to rejection, as they were present in intraocular Ad5E1 tumours, and local depletion of macrophages resulted in progressive tumour growth. Ocular macrophages contributed to Ad5E1 tumour rejection, as Ad5E1 tumour rejection did not occur in macrophage-depleted SCID mice reconstituted with rejector CD4+ T cells. This demonstrates that macrophage and CD4+ T-cell co-operation is needed for non-phthisical rejection of intraocular tumours.     

Induction of PD-L1 on monocytes: A new mechanism by which IVIg inhibits mixed lymphocyte reactions

Allograft rejection and graft-versus-host disease (GvHD) are frequent complications following solid organ or stem cell transplantation in which T cell activation plays a central role. Despite the development of new immunosuppressive drugs that improve the success rate of transplantation, allograft survival continues to be a challenge. Recently, intravenous immunoglobulin (IVIg) has been proposed as prophylaxis and post-transplant treatment to reduce acute rejection episodes. IVIg is a therapeutic agent that is known to down-modulate T cell functions in patients with autoimmune disorders. To test the hypothesis that this immunomodulatory effect could be beneficial in the context of transplantation, we used mixed lymphocyte reactions (MLR) as an in vitro model of allograft rejection and GvHD. Our results show that IVIg strongly inhibits the MLR as evaluated by IL-2 secretion, a well-known marker of T cell activation. IVIg also modulates the secretion of other pro-(IL-6, IFN-γ) and anti-inflammatory (IL-1RA) cytokines. More importantly, we show that IVIg induces monocytes with a CD80^low PD-L1^high phenotype and that blockade of PD-L1 partially abrogates the inhibitory effect of IVIg. We have thus identified a new mechanism by which IVIg inhibits T cell functions in the context of transplantation, supporting the potential usefulness of IVIg in the prevention or treatment of graft rejection and GvHD.     

Endothelial molecules decipher the mechanisms and functional pathways in antibody-mediated rejection

Microvascular endothelium is the main target of injury in antibody-mediated rejection of human organ transplants. Hence, antibody-mediated rejection histologically presents with microvascular inflammation (pulmonary or myocardial or peritubular capillaritis, glomerulitis), thrombosis, and endothelial remodeling (duplication and/or multilayering of glomerular and capillary basement membranes). We previously observed upregulation of several endothelial genes in kidney transplant biopsies from patients with donor specific antibodies, indicating active antibody-mediated rejection and poor graft survival. Furthermore, endothelial molecular signals discovered a previously unknown clinical phenotype: C4d negative antibody-mediated rejection. With the recognition of C4d negative antibody-mediated rejection, data from multiple transplant centers now show that antibody-mediated rejection is the most common cause of late kidney transplant failure. This paper reviews the current understanding of endothelial cell biology in antibody-mediated rejection, emphasizing recent advances and pending questions. Furthermore, the paper discusses functionally active pathways in human antibody-mediated rejection, which include aspects of endothelial activation with increased endothelial adhesive and pro-coagulant signals facilitating leukocyte trafficking and attachment, cell-to-basement membrane interactions, platelet activation, coagulation, and endothelial repair responses. To understand effector mechanisms of antibody-mediated rejection and quantify the degree of antibody-mediated tissue injury in clinical transplants, endothelial cells provide a useful read-out.     

The significance of plasma cell infiltrate in acute cellular rejection of liver allografts

Acute cellular rejections of higher grades of histologic severity are associated with increased risk of graft failure and death after liver transplantation. Plasma cell-rich infiltrates are associated with adverse clinical outcomes in acute renal allograft rejection and in liver allografts without rejection, but there are limited data on plasma cell-rich infiltrates in acute liver allograft rejection. In this study, 59 biopsies of acute liver allograft rejection were confirmed histologically and clinically, independently graded, and the percentage of plasma cells in portal inflammatory infiltrate was objectively assessed using a standardized protocol. Plasma cell infiltrates were observed in 32 (54%) of the specimens, the mean percentage of plasma cells in the infiltrates being 2.97%. Infiltrates with any plasma cells were significantly more common in groups with higher histologic severity of rejection (75% and 100% versus 31% and 48%, P = .006). The mean percentage of plasma cells in the portal infiltrate was also significantly higher in groups with higher histologic severity of rejection (4.95% and 17.82% versus 0.37 and 0.82%, P = .0002). All the biopsies with more than 30% plasma cells in the infiltrate were found to have severe rejection, whereas all with more than 10% plasma cells had either moderate or severe rejection. The association of plasma cell-rich infiltrates with histologic severity of rejection suggests that plasma cell-rich infiltrates could potentially be useful as a marker of severe rejection.     

Lack of association between CTLA-4 and PDCD1 polymorphisms and acute rejection in German liver transplant recipients

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell-death 1 (PDCD1) are two genes encoding coinhibitory immunoreceptors that are involved in regulation transplant rejection and tolerance induction. Thus, CTLA-4 and PDCD1 may be good candidate genes to evaluate in liver transplant rejection. In this retrospective study, we investigated whether four functional single nucleotide polymorphisms (SNP) of the CTLA-4 gene and PDCD1 gene were associated with susceptibility to liver transplant rejection. The SNPs −1772T > C (rs733618), −1661A > G (rs4553808) of the CTLA-4 gene, and the SNPs 7146G > A (rs11568821), 7209C > T (rs41386349) of the PDCD1 gene were genotyped by polymerase chain reaction allele specific restriction enzyme analysis (PCR-ASRA) in 100 liver recipients with acute rejection, 104 liver transplant recipients without acute rejection and 100 healthy control individuals. For the selected SNPs we did not detect any significant difference in genotypic and allelic frequencies between liver transplant recipients with and without acute rejection. In conclusion, our results suggest that the tested SNPs may not be associated with susceptibility to acute liver transplant rejection in a Caucasian population.     

Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection

Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction.