异种移植中超急性排斥反应的机制与防治策略

异种移植是最终解决全球性供体器官严重短缺问题的最有效途径之一.异种移植中的超急性排斥反应(xenogeneic hyperacute rejection,XHAR)与同种异体移植中的ABO血型不合所致HAR类似.现就HAR的发病机制和防治策略进行综述.     

Tregs对同种异体牙移植免疫排斥反应的抑制作用

目的 探讨Tregs对同种异体牙移植术后免疫排斥反应的抑制作用,提供一种免疫移植方法.方法 免疫抑制剂Tregs给予白鼠尾巴静脉注射1周,建立白鼠同种异体牙移植模型,术后观察移植牙存活、排异发生率及程度.结果同种异体牙均诱发免疫排斥反应,但Tregs注射后免疫排斥反应的时间缓慢,组织切片存活时间显著延长（P＜0.01）.结论 使用免疫抑制剂是预防同种异体牙移植免疫排斥反应的有效方案,可以使同种异体牙移植免疫排斥反应延迟,存活时间延长.     

同种异体阴茎移植的研究进展

同种异体移植技术给重建修复外科带来了很大的期望,目前,手、喉、角膜、肾、肝等器官及复合组织同种异体移植在临床实践中取得了很大进步。在组织先天或后天缺损临床应用中显示出很大的潜能。阴茎同体异种移植属复合组织移植的范畴,不同于内脏器官移植,它由各种抗原性不同的组织组成,包括皮肤、肌肉、腱膜、海绵体、神经白膜、血管,有的组织抗原性强,有的组织抗原性弱,其中肌肉、皮肤抗原性最强,容易发生排斥反应,远比心、肝、肾、肺免疫排斥反应强烈,加之异体阴茎免疫排斥反应机制复杂,缺乏排斥反应明确诊断标准及预测指标,使排斥反应难以预测和判断,保护器官移植的免疫机制的剂量不足以保护异体同种阴茎移植,而增加免疫抑制剂的剂量可诱发感染药物毒性及移植物功能衰竭也难以避免,因此在临床应用上受到限制。目前,我们对同种异体阴茎移植、治疗及研究的进展回顾,以期望同种异体研究获得同行的关注与推动。     

非协调性异种气管移植的实验研究

目的探索异种气管移植免疫排斥反应特点,为解决供体气管来源提供新方向,并为研究肺移植继发的气道阻塞性疾病(OAD)建立理想的动物模型。方法建立SD大鼠颈部肌肉瓣包裹移植气管模型,以深低温冻储同种异体气管移植为对照,通过组织化学检查,免疫荧光检查,流式细胞术等方法,观察冷冻与非冷冻豚鼠—大鼠非协调性异种气管移植的成活情况,分析其免疫排斥反应的特点和机制。结果颈部肌肉瓣包裹深低温冻储同种异体SD大鼠长期存活。豚鼠—大鼠冷冻异种气管移植最长成活14 d,平均(13.2±0.75)d;新鲜异种气管移植最长成活9 d,平均(8.0±1.09)d。组织学检查,异体移植气管基本正常,气管通畅度大于80%。异种移植气管呈急性排斥反应表现,移植物大量嗜酸粒细胞,淋巴细胞,单核巨嗜细胞浸润;受体IgM,IgG,C3沉积;外周血CD4+T、CD8+T淋巴细胞明显升高;黏膜上皮剥脱,软骨失去活性;气管通畅度小于50%。以上表现随时间延长而加重,冷冻组弱于非冷冻组。结论细胞免疫反应参与的体液免疫反应为主的急性排斥反应是豚鼠—大鼠非协调性异种气管移植免疫反应特点。深低温冻储消减供体抗原,在一定范围内延长异种移植物成活时间。     

大鼠同种异体肢体移植急性排斥反应的实验研究

目的通过大鼠同种异体肢体移植模型,旨在分析大鼠同种异体肢体移植中各种不同组织的急性排斥反应特点,确定反映肢体移植排斥反应最具有代表性的组织类型.方法将29只Sprague-Dawley成年大鼠随机分成2组,对照组15只为自体肢体再植组,实验组14只为Wistar→SD同种异体肢体移植组,术后不用免疫抑制剂,观察急性排斥反应出现的时间及表现,并对移植肢体中各组织进行组织病理学检查.结果异体肢体移植术后第(3.36±1.15)d开始出现皮下水肿和皮肤红斑,这是最早的急性排斥反应表表现;移植肢体的平均存活时间为(7±0.78)d;移植肢体中皮肤组织的排斥反应程度最强.结论Wistar→SD同种异体肢体移植中皮肤是最具有代表性的、最易于观察排斥反应的组织类型.     

同种异体复合组织移植的免疫研究进展

目的了解同种异体复合组织移植的免疫研究进展。方法查阅相关文献,对同种异体复合组织移植的免疫特点、实验进展、临床经验等进行总结。结果同种异体复合组织位于体表,包含组织成分复杂,抗原性高。其移植后在免疫抑制剂用药方案、排斥反应的诊断以及慢性排斥反应发生率等许多方面同内脏器官移植有不同的特点。结论在下一步研究中,应吸取同种异体复合组织移植独特的经验教训,在诱导耐受、局部用药、排斥诊断等方面树立同种异体复合组织的独特标准。     

蛋白组学与同种异体肾移植排斥反应

生物标记物是最明确、最可靠同时也是最易受影响、最能够预测同种异体移植物动态发展的重要因素,探索早期移植排斥中具诊断敏感性和特异性的生物标记物的蛋白组学研究是近来国内外研究的热点.本文综述了蛋白组学技术的发展以及在同种异体肾移植排斥反应中的应用,为探讨预测和诊断早期同种异体肾移植排斥反应的新策略提供理论依据.     

国外美容医学最新研究与进展(四)

本文收集了2015年有关面部为主的同种异体复合组织移植的国外文献:1复合的同种异体组织移植:现代新进展及预防急性、慢性排斥反应的的研究;2在全脸移植时单一面静脉引流状态的观察:三维计算机图像研究;3通过2年组织学分析,解读面部同种复合组织移植后对黏膜、皮肤进行活检的意义;4应用前哨瓣评估面部同种异体移植后的排斥反应;5面部严重电损伤的修复重建。     

同种异体周围神经移植进展

周围神经损伤在临床上十分常见,而神经损伤造成的缺损仍存在修复的难题,较长的缺损仍需移植体桥接.目前普遍认为周围神经自体移植的效果优于同种异体移植,但长段缺损时存在着供体有限和造成供区功能丧失的缺点,因而近年来一些学者的研究重点已转向同种异体移植的研究.同种异体周围神经移植是否成功,主要取决于有效的降低排斥反应的手段.多年来人们在抗移植排斥反应方面进行了不懈的尝试和探索,如预处理供体神经、使用免疫抑制剂、诱导受体免疫耐受等.     

带血管同种异体骨关节移植研究进展

带血管的同种异体骨关节移植可以引起类似于器官移植的免疫排斥反应,组织配型、冷冻保存及免疫抑制剂的应用对移植骨关节的免疫排斥反应及愈合可产生一定的影响。初步的解剖学研究和临床应用尝试为带血管同种异体骨关节移植的进一步研究和实践提供基础和借鉴。     

异种移植免疫排斥的研究进展

异种移植是解决人体器官严重短缺的重要思路.随着对异种移植排斥和人畜共患感染性疾病的深入研究,以及α-1,3-半乳糖苷转移酶基因敲除猪的成功构建,以猪为供体的异种移植与临床应用之间的距离正在逐渐缩短.阻碍异种移植发展的主要障碍仍是免疫排斥反应.本文试就目前异种免疫排斥的研究进展进行综述,希望对未来的临床异种移植研究提供参...     

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。     

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。     

水苏糖在猪到猴异种心脏移植超急性排斥反应中的作用（附视频）

目的观察水苏糖在猪到猕猴异位心脏移植超急性排斥反应中的作用。方法采用猪到猕猴腹腔内心脏异位移植模型。根据是否经水苏糖处理分为实验组及对照组,每组3只猕猴,观察移植心脏移植后24h内持续搏动时间和组织形态学变化。结果对照组移植心脏持续搏动时间分别为5、15、20min;心肌间质弥漫性出血、水肿,血管扩张,内皮细胞肿胀、坏死。实验组移植心脏持续搏动时间分别为50min、97min和24h;心肌间质未见出血、坏死,血管内皮细胞未见肿胀。结论水苏糖可能对猪到猕猴异位心脏移植的超急性排斥反应有抑制作用。     

Human xenogenic kidney transplantation from the clinical viewpoint]

Pig-to-primate transplantations of hDAF-transgenic kidneys achieved survival times of up to 70 days. Pilot projects for clinical kidney xenotransplantation seem to be possible in the near future. The problems of hyperacute rejection seem to be solved. Delayed xenograft rejection remains a serious problem. Further medical, ethical and practical issues have to be solved, before Phase-I-studies can be anticipated. In contrast to other organs, kidney xenotransplantation is associated with low operative risk. Xenotransplant dysfunction or rejection could be treated with conventional hemodialysis.     

Cardiac xenotransplantation: progress toward the clinic

BACKGROUND: Animal organs could satisfy the demand for solid organ transplants, which currently exceeds the limited human donor supply. Hyperacute rejection, the initial immune barrier to successful xenotransplantation, has been overcome with pig donors transgenic for human complement regulatory proteins. Delayed xenograft rejection, thought to be mediated by anti-pig antibodies predominantly to Gal antigens, is currently regarded as the major barrier to successful xenotransplantation. A median graft survival of 90 days in the life-supporting position is considered a reasonable initial standard for consideration of entry to the clinic. METHODS: A series of 10 heterotopic heart transplants from CD46 transgenic pigs to baboons was completed. Immunosuppression consisted of splenectomy, Rituximab (Anti-CD20), tacrolimus, sirolimus, corticosteroids, and TPC. Thymoglobulin (Rabbit Anti-Thymocyte Globulin) was used to treat putative rejection episodes. RESULTS: Median graft survival was 76 days (range 56-113 days, n = 9). Only three grafts were lost to rejection. The remaining grafts lost were due to recipient mortality with baboon cytomegalovirus (BCMV) being the major cause (n = 4). No cellular infiltrates were present as a manifestation of rejection. Three hearts showed chronic graft vasculopathy. CONCLUSIONS: The median survival of 76 days in this group of heterotopic porcine-to-baboon cardiac xenografts represents a major advance over the median 27-day survival reported in the literature. Cellular rejection may not constitute a direct major barrier to xenotransplantation. A median survival of 90 days may be achievable with better control of BCMV infection. If further studies in the orthotopic position replicate these outcomes, criteria considered appropriate for clinical application of cardiac xenotransplantation would be approached.     

The Role of Macrophages in Xenograft Rejection

Safe and effective xenotransplantation would provide a valuable answer to many of the limitations of allogenic transplantation. Such limitations include scarcity of organ supply and morbidity to donors in cases of living-related donor transplantation. The main hurdle to the efficacious application of xenotransplantation in clinical medicine is the fierce host immune response to xenografts. This immune response is embodied in 3 different types of xenograft rejection. Both hyperacute rejection and delayed xenograft rejection are mediated by natural antibodies and are concerned primarily with whole organ rejection. Cellular xenograft rejection (CXR), on the other hand, is concerned with both whole organ and CXR and is mediated by innate immunity rather than natural antibodies. Macrophages, which are cells of the innate immune system, play a role in all 3 types of xenograft rejection (not just CXR). They impart their effects both directly and through T-cell activation.     

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。     

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.     

中华眼镜蛇毒结合免疫抑制剂控制异种移植排斥反应

目的:探讨协调性和非协调性异种移植免疫排斥不同机理,寻找中华眼镜蛇毒结合免疫抑制药物的最佳治疗方案。方法:采用改良的Heron颈部套袖法分别建立小鼠对大鼠,豚鼠对大鼠异种异位心脏移植模型,受体大鼠各分为4组:1组仅行异种移植不给药;2组联合应用中华眼镜蛇蛇毒因子、环磷酰胺、FK506;3组将2组中华眼镜蛇毒剂量加倍;4组在2组用药组合基础上再加用前列腺素E1。结果:给药组移植供心存活时间明显延长,尤其在小鼠对大鼠模型给予PGE1后(小鼠4组6.92d)及豚鼠对大鼠模型蛇毒因子剂量加倍后(豚鼠3组27.33h)。两类模型给药后CH50,异种抗体IgM明显降低,并逐渐出现急性血管排斥反应改变。结论:异种移植后的超急性排斥反应和急性血管排斥反应存在着密切的相互关联,是统一的排斥过程中具有不同特点的两个阶段。中华眼镜蛇毒联合多种免疫抑制药物可控制异种排斥,尤其对非协调性异种移植有更大的作用。