异种移植领域猪内源性逆转录病毒的研究进展

供体器官来源不足严重阻碍和困扰着器官移植手术的推广和应用，随着免疫学、基因工程与克隆技术的迅速发展，转基因猪的出现，异种移植有望解决器官短缺的问题，但猪内源性逆转录病毒种间传播的可能性必须进一步深入研究，本文就近期相关研究作一综述。     

异种移植领域猪内源性逆转录病毒的研究进展

供体器官来源不足严重阻碍和困扰着器官移植手术的推广和应用,随着免疫学、基因工程与克隆技术的迅速发展,转基因猪的出现,异种移植有望解决器官短缺的问题,但猪内源性逆转录病毒种间传播的可能性必须进一步深入研究,本文就近期相关研究作一综述.     

猪内源性逆转录病毒在异种移植中的感染风险

猪作为异种移植供体可有效解决人类同种移植供体短缺的问题,但猪内源性逆转录病毒具有潜在的感染风险,严重影响了猪器官、组织、细胞在临床中的应用。因此,在异种移植应用于临床前,阐明猪内源性逆转录病毒的感染风险性至关重要。     

异种移植材料中α-gal抗原的研究进展

临床上对于组织损伤、骨缺损等病例,采取移植作为常用的修复方式。虽然自体移植在临床上被广泛的应用,但是其存在着取材量有限,难以实现大范围缺损修复等原因,异种移植被广泛应用于临床。动物来源的移植材料存在着天然的免疫原性,能够引起机体的免疫排斥反应。天然异种抗原α-半乳糖基抗原(Galaetosylα-gal-(1,3)-galaetosylβ-1,4-N-aeetylglueosaminyl,α-gal epitopes,α-gal)是存在于灵长目以外的哺乳动物体内的主要异种抗原,能够引起人体的免疫排斥反应。因此对异种移植材料中α-gal抗原残留量的评价成为迫切需要解决的问题。我们对α-gal的基本特点及近来的研究进展进行了总结。     

异种移植中的免疫学问题及对策

随着临床同种异体移植的深入开展 ,人类供者器官来源与临床需求之间的缺口日益扩大 ,许多研究者逐渐把目标转向了利用动物器官的异种移植。因其具有诸多优点 ,猪成为了移植界公认的替代人类器官的最佳来源。本文将对近年来国外有关异种移植免疫学问题的可能机制及对策的文献作一综述以供参考。     

028 异种移植中的免疫学问题及对策

随着临床同种异体移植的深入开展，人类供者器官来源与临床需求之间的缺口日益扩大，许多研究者逐渐把目标转向了利用动物器官的异种移植。因其具有诸多优点，猪成为了移植界公认的替代人类器官的最佳来源。本文将对近年来国外有关异种移植免疫学问题的可能机制及对策的文献作一综述以供参考。     

胚胎干细胞和异种器官移植——21世纪移植免疫学面临的挑战

1998年美国Ｔｈｏｍｓｏｎ和Ｇｅａｒｈａｒｔ两个实验室分别报告人体胚胎干细胞 (ＥＳ细胞 )和胚胎生殖细胞(ＥＧ细胞 )建系成功 ,由此激起人体ＥＳ细胞定向分化的研究。美国《时代》周刊将此列为 2 0世纪末世界十大科技成就之首 ,并认为ＥＳ细胞和人类基因组将同时成为新世纪最具发展和应用前景的领域。1　ＥＳ细胞的定向分化与移植应用核转移技术 ,人体体细胞核可被植入去核卵母细胞中 ,通过胚泡阶段的发育 ,从中获取内细胞团 (ＩＣＭ ) ,建成ＥＳ细胞系。此体细胞核已被ｒｅ ｐｒｏｇｒａｍｍｅｄ ,具有多潜能性 ,能定向分化成各种细胞…     

猪-猕猴延迟性异种移植排斥反应的发生机制

目的：探讨猪．猕猴延迟性异种移植排斥反应(DXR)的发生机制。方法：建立湖北白猪-云南猕猴的腹腔异位心脏移植模型，应用中华眼镜蛇毒因子(Y-CVF)完全清除受者体内补体，并应用环孢素A(CsA)、环磷酰胺(CTX)和甲泼尼龙(M．P)三联免疫抑制治疗。检测血清C3、C4、抗猪内皮细胞天然抗体，免疫组化方法染色检测移植物中C3、C5b-9、IgG、IgM、细胞间黏附分子-1(ICAM-1)、肿瘤坏死因子-α(TNF-α)、单核巨噬细胞(CD68)、NK细胞(CD57)、CIM T细胞和CD8 T细胞的表达。结果：移植心存活时间分别为8、10、13和13天，血清C3和补体总活性均下降为0，抗猪内皮细胞天然抗体水平在移植后则有一个更为明显的下降，在移植心失功前2～4天开始天然抗体稍有回升，但较术前正常时仍明显偏低。移植心有程度不等的C3、C4、C5b-9、IgG及IgM沉积，大量的单核细胞(50％)，少量的NK细胞(8％～10％)、CD4 T细胞(15％)和CD8 T细胞(25％)。移植物血管内皮细胞表面出现ICAM-1的表达上调，移植物间质中出现TNF-α的表达增加。结论：体液免疫和细胞免疫参与猪-猕猴DXR排斥反应的发生。     

猪作为供体的异种肝移植的研究与进展

背景：猪易于饲养,易繁殖,器官大小与人较匹配,并且可通过基因调控技术来增强供受体器官匹配性,因此猪是最佳异种供体器官的大动物模型。 目的：总结近年来猪作为供体的异种移植研究进展。 方法：应用计算机检索PubMed数据库及万方数据库2001-01/2010-12有关以猪及非人类灵长类为供体进行异种移植的文献报道。 结果与结论：使用猪作为供体的异种移植应用于临床可能会缓解供体器官短缺的问题,然而异种移植免疫学方面还存在某些障碍,可通过基因工程技术和开发新型免疫抑制剂来解决。至此所进行的研究还不能完全克服免疫排斥反应,并且除免疫因素外,还有异种病原的感染问题,如猪内源性反转录病毒。现在还不能确定是否具有潜在的感染性,随着进一步的研究,将会彻底克服免疫排斥和病毒感染等问题。     

异种胰岛移植的免疫耐受诱导

胰岛移植能够纠正DDM的高血糖并减少糖尿病相关并发症,临床广泛应用将造成尸源性胰腺供体严重不足,动物来源的胰岛将成为今后胰岛的主要供源.异种移植的最大障碍是移植排斥反应,目前控制异种胰岛移植的免疫抑制治疗无法在临床推广.啮齿动物实验研究证明异种胰岛移植不需要长期重度免疫抑制治疗就能获得生存;杂交系动物实验研究提示异种胰岛移植的临床应用是可行的.随着对大动物杂交种系间异种移植排斥机理和动物病原体传播能力的深入了解,异种胰岛移植将进入临床.     

Inhibition of porcine endogenous retroviruses by RNA interference: increasing the safety of xenotransplantation

Transplantation of porcine xenografts into human recipients is a realistic option to overcome the growing worldwide shortage of suitable allogeneic organs. However, there remains the risk of infection by porcine endogenous retroviruses (PERVs) that cannot be eliminated like that by other microorganisms by breeding pigs under specified pathogen-free conditions. To reduce the release of PERVs by porcine transplants, a new approach, RNA interference (RNAi), was applied. Here, we show significant reduction of PERV expression by synthetic short interfering RNAs (siRNAs) corresponding to different parts of the viral genes gag, pol, and env. The most inhibitory sequences were selected and expressed as short hairpin RNAs (shRNAs) by a polymerase III vector system leading to persistent suppression of PERV replication. Cells or organs from transgenic pigs producing such shRNAs should increase the safety of xenotransplantation.     

Recent advances in the immunology of xenotransplantation

The transplantation of tissue and organs between individuals of different species, that is xenotransplantation, engenders a variety of severe immune responses. Xenogeneic immune responses mediated by naturally occurring antibodies and complement lead to hyperacute and acute vascular rejection of vascularized organ grafts and may also cause vascular rejection of cell and tissue grafts. Under some circumstances, however, a vascularized organ graft may evade humoral rejection despite the presence of antidonor antibodies in the circulation of the recipient; this condition is called accommodation. Xenogeneic immune responses mediated by T-lymphocytes and natural killer cells may cause acute cellular rejection. The extent to which cellular rejection of xenografts resembles cellular rejection of allografts remains to be determined. New insights into the molecular mechanisms underlying the immune responses to xenotransplantation have shed new light on the pathogenesis of immunological disease and have allowed the development of specific immunomodulatory strategies that may facilitate clinical application of xenotransplantation.     

Preclinical rationale and current pathways to support the first human clinical trials in cardiac xenotransplantation

Recent initiation of the first FDA-approved cardiac xenotransplantation suggests xenotransplantation could soon become a therapeutic option for patients unable to undergo allotransplantation. Until xenotransplantation is widely applied in clinical practice, consideration of benefit versus risk and approaches to management of clinical xenografts will based at least in part on observations made in experimental xenotransplantation in non-human primates. Indeed, the decision to proceed with clinical trials reflects significant progress in last few years in experimental solid organ and cellular xenotransplantation. Our laboratory at the NIH and now at University of Maryland contributed to this progress, with heterotopic cardiac xenografts surviving more than two years and life-supporting cardiac xenografts survival up to 9 months. Here we describe our contributions to the understanding of the mechanism of cardiac xenograft rejection and development of methods to overcome past hurdles, and finally we share our opinion on the remaining barriers to clinical translation. We also discuss how the first in human xenotransplants might be performed, recipients managed, and graft function monitored.     

Advances in mechanisms of asthma, allergy, and immunology in 2011

2011 was marked by rapid progress in the identification of basic mechanisms of allergic disease and the translation of these mechanisms into human cell systems. Studies published in the Journal of Allergy and Clinical Immunology this year provided new insights into the molecular determinants of allergenicity, as well as the environmental, cellular, and genetic factors involved in sensitization to allergens. Several articles focused on mechanisms of allergen immunotherapy and the development of novel strategies to achieve tolerance to allergens. Additional studies identified substantial contributions from T(H)17-type cells and cytokines to human disease pathogenesis. Finally, new therapeutic applications of anti-IgE were identified. The highlights of these studies and their potential clinical implications are summarized in this review.     

The infectivity and host range of the ecotropic porcine endogenous retrovirus, PERV-C, is modulated by residues in the C-terminal region of its surface envelope protein

Endogenous retroviral genetic material serves as a reservoir for the generation of retroviral pathogens by recombination between activated endogenous or exogenous infectious agents. Some porcine tissues actively express infectious porcine endogenous retroviruses (PERVs). Of the three classes of PERV characterized to date, two, PERV-A and B, are capable of infecting human cells in vitro, whereas PERV-C cannot. Here, we demonstrate that the PERV-C envelope surface protein (SU) when disassociated from its C-terminus binds human cells. Further, we show that PERV-C binding to human cells is not inhibited in 293 cells productively infected with PERV-A, confirming that the molecule PERV-C interacts with on human cells is distinct from that used by PERV-A. Moreover, we demonstrate that the envelope region encompassing the proline-rich region is required for binding to cells in addition to the putative variable region A (VRA) and B (VRB). The region in the C-terminus of the SU that alters the binding and infectivity properties of PERV-C differs by only nine residues from the analogous region of PERV-A. Caution may be warranted even when a xenotransplantation product is from source pigs that do not express human-tropic viruses, as minimal mutations within PERV-C combined with selection in a human recipient could render PERV-C infectious in humans.