克服异种移植免疫排斥的研究进展

目的 综述克服异种移植免疫排斥的方法.方法 广泛查阅近年国内外克服异种移植免疫排斥的相关文献,并进行总结与分析.结果 目前对异种移植免疫排斥机制和分子生物学技术的研究,为解决异种移植免疫排斥提供了新的思路.结论 异种器官移植应用于临床仅是时间问题.     

异种器官移植免疫生物学研究进展

异种器官移植是解决器官移植短缺的有效手段之一,猪作为潜在的器官移植供体来源已得到广泛认可,但是要实现猪至灵长类动物的异种器官移植的临床应用需要克服多重免疫生物学障碍。本文以异种器官移植多重免疫排斥反应发生的时间先后为顺序,依次对超急性排斥反应、急性体液异种移植排斥反应和急性细胞排斥反应、血栓性微血管病和慢性排斥反应的研究进展进行了综述。     

异种移植中的排斥反应及其对策研究进展

随着器官移植技术在临床的广泛应用 ,同种异基因器官供体远不能满足受体的需要 ,异种移植有可能解决这一矛盾。非灵长类动物 ,特别是猪 ,因其易于饲养 ,且器官大小及免疫学、生理学特性与人类有一定的相似性 ,作为最适的异种移植器官供体已日益引起人们的关注[1,2 ] 。但由于人类和猪两种源间存在巨大的抗原差异 ,针对异种移植物的免疫应答比对同种移植物更加强烈。本文现对近年来有关异种移植排斥机制及其防治策略作一简要回顾。一、异种移植排斥机制1.超急性排斥反应 (hyperacuterejection,HAR):HAR以血栓形成、出血及异种移植物破坏为…     

异种移植的研究进展

供体器官和细胞的匮乏限制了临床同种移植的发展.开展以猪为供体的异种移植研究是缓解供体短缺的重要方法.目前,猪的胰岛细胞、神经元细胞、肝细胞和角膜移植已初步应用于临床,但实体器官移植,如心脏、肝脏、肾脏等仍存在较大的免疫障碍和生理屏障,距离临床应用尚有不小的差距.随着表达一种或多种人的免疫和凝血调节基因猪的出现,异种移植研究取得显著进展,受体和移植器官的存活时间明显延长,而种间交叉感染的风险也较低,但免疫排斥和生理屏障仍是阻碍异种移植进入临床应用的最大障碍.本文就当前异种移植临床前研究的最新进展作一综述,希望能为相关研究者提供一些参考.     

五指山小型猪近交系异种移植产业化研发进展

为了早日实现五指山小型猪(WZSP)近交系异种移植产业化目标,努力推进近交繁育获得近交系,同时开展克服异种移植免疫排斥和猪内源性逆转录病毒(PERV)传染生物安全性两大难题的研发内容。本文从WZSP近交系双基因敲除克隆猪繁育成功、猪-猴异种角膜内皮移植取得突破性进展、WZSP近交系PERV无传染性群体建立、WZSP近交系是理想的动物模型和异种移植供体等方面,介绍WZSP近交系异种移植产业化的研发进展。     

猪胰岛异种移植的研究进展

糖尿病是严重威胁人类健康的疾病,而胰岛移植可以通过调节内源性胰岛素的分泌,治疗1型糖尿病。由于人源胰腺供体不足,无法满足大批量胰岛细胞移植需求。猪胰岛素与人胰岛素仅差1个氨基酸,在糖尿病患者身上使用已有较长历史,而且猪可以进行基因修饰,减少移植后免疫排斥反应,因此目前猪胰岛作为异种胰岛移植来源进入临床试验阶段。本文将就猪-非人灵长类移植的发展史,猪胰岛异种移植中存在的问题、解决方案和研究进展,及猪胰岛异种移植前景和展望做一综述。     

异种移植中转基因动物策略研究进展

近年来 ,在同种移植研究的基础上 ,异种移植的研究也进行了大量的工作 ,突出的成绩表现在异种移植免疫障碍阶段的划分和定义 ,即超急排斥反应、急性血管排斥 (有时也称延迟排斥 )、细胞排斥或慢性排斥、生理功能及其它。根据异种移植免疫学理论 ,利用转基因技术 ,建立转基因动物克服超急免疫排斥是异种移植研究的又一进步 ,显示转基因动物具有很大的发展前景 ,使异种移植走进临床成为可能。本文将就近年异种移植免疫学理论及根据其机制、利用转基因动物克服免疫排斥研究状况作一综述。     

猪内源性反转录病毒与异种移植的安全性

人们已成功地将猪心脏瓣膜移植入人体内 ,猪皮肤已作为烧伤患者的暂时覆盖物 ,猪胰岛细胞已被植入糖尿病患者体内 ,异种移植已展现出十分诱人的前景。但猪→人异种移植主要存在三方面的问题 :( 1)免疫排斥反应 ,包括超急性排斥反应 (ＨＡＲ)、延迟性异种移植排斥反应 (ＤＸＲ)、Ｔ细胞介导的排斥反应 (ＴＭＲ) ;( 2 )猪→人生物学组分的相容性 ;( 3)种间交叉感染病毒的安全性。尤其令人关注的是潜在性和内源性反转录病毒的生物安全性。自上世纪 90年代以来 ,由于对异种移植超急性排斥反应的发生机理有了更深入的研究 ,也有赖于分子生物学、…     

异种移植中转基因动物策略研究进展

近年来,在同种移植研究的基础上,异种移植的研究也进行了大量的工作,突出的成绩表现在异种移植免疫障碍阶段的划分和定义,即超急排斥反应,急性血管排斥（有时也称延迟排斥）,细胞排斥或慢性排斥,生理功能及其它,根据异种移植免疫学理论,利用转基因技术,建立转基因动物克服超急免疫排斥是异种移植研究的又一进步,显示转基因动物具有很大的发展前景,使异种移植走进临床成为可能,本文将就近年异种移植免疫学理论及根据其机制,利用转基因动物克服免疫排斥研究状况作一综述。     

异种肝移植的历史与发展

异种移植是解决同种供体器官短缺的重要途径。以α-1,3-半乳糖基转移酶基因敲除(GTKO)小型猪为供体、非人灵长类动物为受体的心脏和肾移植,最长存活达945 d和136 d,但肝移植尚无长期存活报道。国内外研究表明,免疫排斥和凝血调节障碍仍是阻碍移植肝和受体长期存活的主要原因。本文总结异种肝移植的发展历程,分析目前存在的问题,为未来的临床异种移植研究提供参考。     

气管异种移植的现状

气管异种移植目前还处于动物实验阶段,尚不能应用于临床,主要原因是异种气管移植后的免疫排斥问题未能解决,社会伦理学方面还存有争议。移植气管的保存与再血管化也是当前所面临的主要问题。其中,能否解决移植后宿主对气管的免疫排斥是移植成败的关键。该文通过介绍异种气管移植的概况,了解其研究进展及所面临的挑战。     

A highly reproducible cervical cuff technique for rat‐to‐mouse heterotopic heart xenotransplantation

Xenotransplantation is an effective way to solve the problem of donor shortage in clinical transplantation. However, clinical use of xenotransplantation is currently limited due to immunological challenges such as acute vascular rejection and cell‐mediated rejection. To finally surpass this immunological barrier, more preclinical research is needed into the molecular mechanisms of rejection and the possible effects of new immunosuppressants. Our aim was to create a refined, highly reproducible protocol to establish the most suitable rat‐to‐mouse heterotopic heart transplantation model using the cuff technique.     

异种器官移植的新进展

目的总结异种器官移植的新进展。方法分析近年来异种器官移植进展的文献报道。结果随着免疫生物学的深入研究,异种器官移植取得了长足的进步,并开始应用于临床,但免疫排斥反应的诸多问题仍在探寻之中。结论异种移植为解决器官衰竭患者移植器官短缺的问题展现了广阔的前景,如何更有效地抑制排斥反应及延长移植物生存期是今后研究的重点。     

The sweets standing at the borderline between allo‐ and xenotransplantation

Animal cells are densely covered with glycoconjugates, such as N‐glycan, O‐glycan, and glycosphingolipids, which are important for various biological and immunological events at the cell surface and in the extracellular matrix. Endothelial α‐Gal carbohydrate epitopes (Galα3Gal‐R) expressed on porcine tissue or cell surfaces are such glycoconjugates and directly mediate hyperacute immunological rejection in pig‐to‐human xenotransplantation. Although researchers have been able to develop α1,3‐galactosyltransferase (GalT) gene knockout (KO) pigs, there remain unclarified non‐Gal antigens that prevent xenotransplantation. Based on our expertise in the structural analysis of xenoantigenic carbohydrates, we describe the immunologically significant non‐human carbohydrate antigens, including α‐Gal antigens, analyzed as part of efforts to assess the antigens responsible for hyperacute immunological rejection in pig‐to‐human xenotransplantation. The importance of studying human, pig, and GalT‐KO pig glycoprofiles, and of developing adequate pig‐to‐human glycan databases, is also discussed.     

The immunological hurdles to cardiac xenotransplantation

The main hurdle to clinical application of cardiac xenotransplantation is the immune response of the recipient against the graft. Although all xenografts arouse an intense immune response, the effect of that response depends very much on whether the graft consists of isolated cells or an intact organ, such as the heart. Intact organs, which are transplanted by primary vascular anastomosis, are subject to severe vascular injury owing to the reaction of immune elements with the endothelial lining of donor blood vessels. Vascular injury leads to hyperacute rejection, acute vascular rejection, and chronic rejection. The immunological basis for these types of rejection and potential therapies, which might be used to avert them, are discussed.     

Xenotransplantation of the liver]

The development of pigs transgenic for human regulators of complement activation resulted in the nearly total elimination of episodes of hyperacute rejection following discordant solid organ xenotransplantation. Following discordant heart or kidney transplantation, in subhuman primates, graft survival rates of up to several months can be observed. In contrast to these organs, the xenotransplantation of the liver is associated with the inherent problem of the immunological and metabolic compatibility of the large variety of xenoproteins generated. Based on a review of data mainly derived from experimental ex-vivo xenoliver perfusions in patients with hepatic coma, whole organ orthotopic or heterotopic liver xenotransplantation currently is not likely to become a relevant option for the treatment of patients with endstage liver failure. In contrast, clinical studies utilizing different forms of bioartificial liver assist devices are currently underway. Based on preliminary data published, this form of liver support therapy might enter the clinic in the near future.     

Xenotransplantation: immunological barriers and strategies to overcome them

Hyperacute and acute vascular rejection of xenografts are well defined barriers to clinical pig‐to‐human xenotransplantation. Enormous progress has been made in recent years to overcome these immunological barriers. For example, transgenic expression of human complement regulatory molecules (e.g. CD46, CD55) in pigs has been shown to be an effective strategy to prevent hyperacute rejection in pre‐clinical models of xenotransplantation. Alpha1,3‐galactosyltransferase knock‐out pigs are available and provide a second possibility to avoid hyperacute rejection mediated by pre‐existing antibodies. Furthermore, transfer of protective genes (e.g. A20, HO‐1) to endothelial cells is expected to reduce their susceptibility to effector mechanisms leading to acute vascular rejection. In addition, the efficiency of strategies to avoid coagulation/thrombosis after pig‐to‐human xenotransplantation (e.g. transgenic expression of human thrombomodulin, CD39) is currently tested. Thus, for further development of clinical xenotransplantation immunological concepts are now required facilitating the control of human anti‐pig cellular immune responses. Our group focuses on the inhibition of human anti‐pig T cell responses by targeting “negative” costimulatory pathways. We tested the hypothesis that overexpression of the human negative costimulatory ligands PD‐L1 and PD‐L2 on pig antigen presenting cells will result in reduced human anti‐pig T cell responses. The data so far show that (i) human CD4⁺ T cells respond with reduced proliferation and cytokine synthesis to PD‐L1/PD‐L2 expressing pig cells, (ii) PD‐L1/PD‐L2 pig transfectants induce human regulatory T cells (T_reg) which suppress the activation of conventional T cells, and (iii) PD‐L1/PD‐L2 expressing pig cells are protected from lysis mediated by CD8⁺ human cells. Together these observations support the assumption that transgenic expression of human PD‐L1 and/or PD‐L2 in pig cells and tissues could be an approach to prevent T cell reactivity after pig‐to‐human xenotransplantation. Supported by the Deutsche Forschungsgemeinschaft (Transregio Forschergruppe “Xenotransplantation”, FOR 535).     

异种移植的研究进展

目的总结异种移植的研究现状与进展。方法复习国内外关于异种移植研究的相关文献并进行综述。结果超急性异种排斥反应是异种移植面临的巨大问题,器官或组织的供体经过基因修饰后,在一定程度上可以减轻超急性异种排斥反应。由于不同的器官具有不同的特性,目前异种器官移植移植物的存活时间存在较大差异。结论通过对相关异种移植实验研究的分析,可以全面地了解异种移植的研究背景,为异种移植提供合适的研究方向。将经基因修饰的动物作为异种器官或组织的供体,有望使移植物避免或减轻超急性异种排斥反应。     

Xenogeneic ex vivo hemoperfusion of rhesus monkey livers with human blood

Abstract In order to copy the clinical situation of concordant xenotransplantation, Rhesus Monkey livers were hemoperfused with human blood. Changes of immunological (TNFα, IL-1β, IL-2, IL-2R, IL-6, IFNy, TXB2, 6kPGF1α, sICAM-1, SELAM-1, sHLA-I-Ag) and pathophysiological (GOT, GPT, LDH, CK) parameters were followed. Our experiment proves that all phenomena start in the first hour of xenogeneic blood circulation. Xenogeneic rejection in our concordant system is surprisingly severe. Preformed natural antibodies only cannot be the reason of such a damage [5, 6]. We think that beside other important immunological mechanisms, humoral mediators play a considerable role at the beginning of a xenogeneic rejection.     

Progress in multiple genetically modified minipigs for xenotransplantation in China

Pig‐to‐human organ transplantation provides an alternative for critical shortage of human organs worldwide. Genetically modified pigs are promising donors for xenotransplantation as they show many anatomical and physiological similarities to humans. However, immunological rejection including hyperacute rejection (HAR), acute humoral xenograft rejection (AHXR), immune cell–mediated rejection, and other barriers associated with xenotransplantation must be overcome with various strategies for the genetic modification of pigs. In this review, we summarize the outcomes of genetically modified and cloned pigs achieved by Chinese scientists to resolve the above‐mentioned problems in xenotransplantation. It is now possible to knockout several porcine genes associated with the expression of sugar residues, antigens for (naturally) existing antibodies in humans, including GGTA1, CMAH, and β4GalNT2, and thereby preventing the antigen‐antibody response. Moreover, insertion of human complement‐ and coagulation‐regulatory transgenes, such as CD46, CD55, CD59, and hTBM, can further overcome effects of the humoral immune response and coagulation dysfunction, while expression of regulatory factors of immune responses can inhibit the adaptive immune rejection. Furthermore, transgenic strategies have been developed by Chinese scientists to reduce the potential risk of infections by endogenous porcine retroviruses (PERVs). Breeding of multi‐gene low‐immunogenicity pigs in China is also presented in this review. Lastly, we will briefly mention the preclinical studies on pig‐to‐non‐human primate xenotransplantation conducted in several centers in China.