An Update on Xenotransplantation

Xenotransplantation is one of the possible avenues currently being explored to address the shortage problem of human organs. With this in mind, this article will briefly review the current situation with respect to the immunological, physiological and biosafety aspects related to the transplantation of pig organs into primates.Acute humoral xenograft rejection (AHXR) currently remains the central immunological obstacle and the development of strategies for both a better control of the elicited anti-pig humoral immune response or the prevention of the onset of coagulation disorders that accompany AHXR are the two primary focuses of research. To date, porcine xenografts have been shown to sustain the life of nonhuman primates for several months. Such preclinical studies have also demonstrated the absence of insurmountable physiological incompatibilities between pig and primate. In addition, reassuring findings regarding biosafety aspects have been generated and pro-active research aimed at the identification of an organ source with a higher safety profile is also underway.These advancements, in conjunction with ongoing research in pig genetic engineering, immunosuppression and tolerance are expected to further extend the survival of porcine xenografts transplanted into primates. However, until further physiological, efficacy and safety data are generated in relevant primate models, clinical xenotransplantation should not be considered.     

产业转型期规模猪场建设工程防控技术思考

非洲猪瘟和环保的双重影响刺激了中国养猪业快速向集约化、高效化和自动化方向转型,而舍间交叉感染、疫病难控、环境污染等问题依然未能得到有效解决。在猪场建设和管理中,人们的关注重点主要有疾病控制、粪污臭气治理和无抗饲料三个方面,分别对应着生物安全、环保安全和食品安全三个安全底线。在重视猪场生物安全体系建设时,人们往往忽视工程防控技术措施的整体应用,其贡献尚无法得以很好的体现。文章从工程技术的角度,分析了隔离、合理分区和防止交叉感染等对猪场生物安全防控的作用,为猪场的工程防疫体系建设、守住三个安全底线提供指导。     

The perspectives for porcine-to-human xenografts

The shortage of donated human organs for transplantation continues to be a life threatening problem for patients suffering from complete organ failure. Although this gap is increasing due to the demographic changes in aging Western populations, it is generally accepted that international trading in human organ is not an ethical solution. Alternatives to the use of human organs for transplantation must be developed and these alternatives include stem cell therapy, artificial organs and organs from other species, i.e. xenografts. For practical reasons but most importantly because of its physiological similarity with humans, the pig is generally accepted as the species of choice for xenotransplantation. Nevertheless, before porcine organs can be used in human xenotransplantation, it is necessary to make a series of precise genetic modifications to the porcine genome, including the addition of genes for factors which suppress the rejection of transplanted porcine tissues and the inactivation or removal of undesirable genes which can only be accomplished at this time by targeted recombination and somatic nuclear transfer. This review will give an insight into the advances in transgenic manipulation and cloning in pigs--in the context of porcine-to-human xenotransplantation.     

Porcine endogenous retroviruses (PERV): in vitro artifact or a big problem for xenotransplantation?]

The pig is the favorized donor species for clinical xenotransplantation. However, PATIENCE et al. could show, that porcine endogenous retroviruses (PERV), released by a porcine kidney cell line, are capable of infecting human cell lines in vitro. Based on this discovery there is an ongoing discussion concerning the risks of zoonosis combined with xenotranplantation, which culminated in the demand for a moratorium on clinical transplantation of porcine organs. Recent findings exclude the possibility of an artifact due to the use of an immortalized cell line: Release of infectious PERV was also shown for mitogenic stimulated primary porcine peripheral blood mononuclear cells and, even more important, for primary porcine endothelial cells. In contrast, none of the recent retrospective in vivo studies showed evidence for PERV transmission, neither in patients after transplantation of porcine pancreas islet cells or after extracorporal perfusion of porcine kidneys, nor in baboons after transplantation of porcine endothelial cells. Currently it is not known, whether impairments of the immunological responses against foreign pathogens, which are associated with different xenotransplantation strategies, could enable PERV in vivo infection. Only in vivo experiments, if possible in suitable subhuman primate models, offer the prospect for a final risk assessment.     

Transgenic pigs for xenotransplantation for humans]

Transgenic livestock have been generated via microinjection of DNA-constructs into pronuclei of zygotes. However, efficiency is low and only 1-3% transgenic offspring are to be obtained. Integration of the transgene occurs at random and expression is independent from the number of integrated copies but can be affected by the integration site. To overcome the shortage of human organs, transgenic pigs have been generated that express human complement regulatory genes. This approach enables to overcome the hyperacute rejection response as shown by an average survival rate (40-90 days) of the immunosuppressed primate recipients receiving a heart from a transgenic pig. It is expected that transgenic pigs would be available as organ donors in the next 5-10 years. A major prerequisite, however, is the prevention of the potential transfer of pathogenic microorganisms, in particular porcine endogenous retroviruses (PERV). Improvements of the efficiency in the generation of transgenic pigs will be achieved by the use of genetically modified donor cells in nuclear transfer technology (cloning).     

Xenotransplantation and the potential risk of xenogeneic transmission of porcine viruses.

The clinical success of allotransplantation and the shortage of donor organs have led to a proposal for the use of animal organs as alternative therapeutic materials for humans. In that regard, swine are preferable to non-human primates as a source of donor organs. While applications for clinical trials for xenotransplantation have not yet been received in Canada, several trials have already been authorized in the United States. A major concern, however, is the potential for xenogeneic transmission of viruses from animals to humans via organ, tissue, or cellular transplantation or via ex vivo exposure of humans to porcine biologic materials. Xenotransplantation allows viruses to bypass the normal immunological defense mechanisms of the recipient. Furthermore, the use of immunosuppressive drugs following transplantation may facilitate the xenogeneic transmission of zoonotic agents. Of porcine viruses, swine hepatitis E virus does not cause any clinical symptoms in the natural host but is a likely zoonotic agent that can infect humans and cause hepatitis. Porcine circovirus type 1 is prevalent in swine populations with no known association with clinical disease, while circovirus type 2 causes post-weaning multi-systemic wasting syndrome. Porcine endogenous retrovirus is integrated into the host chromosomes while porcine cytomegalovirus undergoes latent infection. Two additional porcine herpesviruses have recently been identified in swine and have been named porcine lymphotrophic herpesviruses. These herpesviruses can potentially become reactivated in human recipients after xenotransplantation. All in all, there are a number of viruses in swine that are of primary concern to screen and eliminate from xenotransplantation protocols. Epidemiology and the current knowledge on xenogeneic risk of these viruses are discussed.     

Primates as experimental animals

The term "primates" comprises a varied group of animals, consisting of more than 250 different species. The close evolutionary relationship to man resulted in the use of nonhuman primates as subjects of study for scientists from different research fields. In biomedical research the use of primates is restricted to questions which cannot be answered by animals with less developed physiological senses. Primates play an important role in infectious disease research, as many pathogens relevant to humans can be transferred to selected primate species. In the last few decades this applied especially for HIV-infections of man, viral hepatitides, herpesvirus infections and for quite a long time for agents of transmissible spongiform encephalopathies, too. In neurobiology, primates play an outstanding role due to the morphological-structural and functional resemblance of their CNS to that of man. Due to new developments in biomedicine, in particular in the field of gene therapeutics, it has to be expected that primates will have to be used also in future as animal models for the welfare of human health.     

浅谈猪繁殖与呼吸综合征的防控措施

猪繁殖与呼吸综合征(Porcine reproductive and respiratory syndrome,PRRS)是由猪繁殖与呼吸综合征病毒(PRRSV)引起的猪的一种高度传染性疾病,又称"猪蓝耳病"。笔者通过引种管理、生物安全、生产流程、疫苗免疫以及实验室监测这五项措施帮助不同的猪场实现对猪蓝耳病的有效防控。     

规模猪场防控非洲猪瘟的生物安全措施

猪场的生物安全措施对该场的疫病预防和控制起到了非常重要的作用。文章介绍了在非洲猪瘟背景下，猪场需要在人员生物安全意识、猪群健康、猪场入口处、猪场出口处、猪场车辆管理等方面需要采取的一系列生物安全措施。供大家参考，以期提升猪场的生物安全管理水平，提高猪场疫病预防控制能力。     

A review of porcine tonsils in immunity and disease

The porcine tonsils are a group of lymphoepithelial tissues located at the common openings of the gastrointestinal and respiratory tracts. The tonsils participate in a variety of functions involving innate, cellular and humoral immunity at the local and systemic levels. Among these immunological functions is the continuous surveillance for the presence of foreign antigens at the openings of the gastrointestinal and respiratory tracts. Within the pig, the movement of lymphocytes, cytokines and chemotactic molecules from the tonsils to other lymphoid organs confers immunity to other portals of pathogen entry and facilitates an efficient and rapid systemic immune response. In spite of the immunological nature of the tonsils, some microorganisms have acquired adaptations that allow them to circumvent the tonsillar immune defenses and utilize the tonsils as a site of entry, replication and colonization. Several bacterial and viral pathogens persist asymptomatically within the tonsils, making identification of asymptomatic carrier animals difficult in disease control and/or pathogen elimination. This paper reviews the current information on the anatomy, immunology and pathobiology of porcine tonsils and discusses the tonsils as a site of pathogen entry, replication and colonization using Salmonella spp., classical swine fever virus and porcine reproductive and respiratory syndrome virus as examples.     

An overview of molecular and cellular mechanisms associated with porcine pregnancy success or failure

Prenatal mortality remains one of the major constraints for the commercial pig industry in North America. Twenty to thirty per cent of the conceptuses are lost early in gestation and an additional 10-15% is lost by mid-to-late gestation. Research over the last two decades has provided critical insights into how uterine capacity, placental efficiency, genetics, environment, nutrition and immune mechanisms impact successful conceptus growth; however, the exact cause and effect relationship in the context of foetal loss has yet to be determined. Similar to other mammalian species such as the human, mouse, rat, and primates, immune cell enrichment occurs at the porcine maternal-foetal interface during the window of conceptus attachment. However, unlike other species, immune cells are solely recruited by conceptus-derived signals. As pigs have epitheliochorial placentae where maternal and foetal tissue layers are separate, it provides an ideal model to study immune cell interactions with foetal trophoblasts. Our research is focused on the immune-angiogenesis axis during porcine pregnancy. It is well established that immune cells are recruited to the maternal-foetal interface, but their pregnancy specific functions and how the local milieu affects angiogenesis and inflammation at the site of foetal arrest remain unknown. Through a better understanding of how immune cells modulate crosstalk between the conceptus and the mother, it might be possible to therapeutically target immune cells and/or their products to reduce foetal loss. In this review, we provide evidence from the literature and from our own work into the immunological factors associated with porcine foetal loss.     

猪源β-防御素2和3的研究进展

防御素是一类阳离子抗菌肽,广泛存在于动物和植物体内。猪源β-防御素2和β-防御素3能抵抗猪体内病原微生物,并能调节机体免疫功能,对生殖发育也有一定的生理作用。猪源β-防御素2能促进仔猪生长,对猪红细胞毒性低,能在毕赤酵母中高效表达,其转基因猪也具有较好的抗病性能。因此,猪防御素具有潜在的应用价值。本文就猪源β-防御素2和β-防御素3在体内的表达分布和调控因素、参与调节的信号通路、在生殖发育和畜牧养殖方面的新功能及应用潜力进行综述。     

生猪保险查勘定损工作中的生物安全风险防范措施探讨

在非洲猪瘟防控新形势下,各猪场都高度重视生物安全,对生物安全风险防范工作提出了新的要求。在这种情况下,过去生猪保险查勘定损中的一些传统做法已经不能适应新形势,出现了猪场封闭式管理和查勘定损工作相冲突,病死猪理赔监督不到位、死亡原因不明、处理不及时以及部分查勘员生物安全意识淡薄等现象。对此,有关部门和机构应加强生物安全培训,采用网络和电子化等手段变革传统工作方式,在保险机构和畜牧兽医部门间加强联动和信息共享,把查勘定损、无害化处理和疫病监测溯源工作有机结合,把生物安全风险降到最低。     

NONHUMAN PRIMATE EXCRETORY UROGRAPHY*

Survey radiographs have not accurately identified renal contour or location in nonhuman primates. Excretory urography using 786 to 1193 mg iodinelkg body weight resulted in dense opacification of the renal parenchyma and pelvis. Abdominal compression improved visu- alization of the renal pelvis. Interpretation of the nonhuman primate excretory urogram was compromised by several anatomic characteristics of this animal group. Superimposition of the kidneys on the lateral radiograph limited evaluation of the renal contour. Since the renal pelvis in most species of nonhuman primates does not possess diverticula (as in the dog and cat) or a caliceal system (as in the pig and man), the diagnosis of pyelonephritis or renal mass lesions was difficult. Severe irregularities in the renal contour, size of the renal pelvis, or areas of deficient concentrating ability were identifiable in nonhuman primate excretory urograms, but the diagnosis of small cysts was not possible in smaller nonhuman primates. The presence of a caliceal collecting system in the spider monkey (Ateles sp.) suggests this animal as a potential model for the evaluation of human renal disease.     

猪卵母细胞超低温冷冻保存技术研究进展

猪卵母细胞有其特殊的生理构造,其冷冻效率一直很低,有关猪卵母细胞冷冻保存的研究尚处在探索阶段。猪卵母细胞冷冻保存方法,主要有快速冷冻和玻璃化冷冻两种,后者的冷冻效果似乎要优于前者,暗示着玻璃化冷冻在猪上的应用可能比程序化法更为优越。在玻璃化冷冻方面,包括OPS法、微滴法和电镜铜网法等,都是在冷冻载体上加以改进。此外,在冷冻保护剂、冷冻程序等方面,仍需要改进和优化,以期进一步提高猪卵母细胞的冷冻效率。     

Implications of simian retroviruses for captive primate population management and the occupational safety of primate handlers.

Nonhuman primates can be naturally infected with a plethora of viruses with zoonotic potential, including retroviruses. These simian viruses present risks to both captive nonhuman primate populations and persons exposed to nonhuman primates. Simian retroviruses, including simian immunodeficiency virus, simian type D retrovirus, simian T-lymphotropic virus, and gibbon ape leukemia virus, have been shown to cause clinical disease in nonhuman primates. In contrast, simian foamy virus, a retrovirus that is highly prevalent in most nonhuman primates, has not been associated with clinical disease in naturally infected primates. Although it has been shown that human retrovirus infections with human T-lymphotropic virus and human immunodeficiency virus originated through multiple independent introductions of simian retroviruses into human populations that then spread globally, little is known about the frequency of such zoonotic events. In this article, exogenous simian retroviruses are reviewed as a concern for zoo and wildlife veterinarians, primate handlers, other persons in direct contact with nonhuman primates, and other nonhuman primates in a collection. The health implications for individual animals as well as managed populations in zoos and research institutions are discussed, the cross-species transmission and zoonotic disease potential of simian retroviruses are described, and suggestions for working safely with nonhuman primates are provided.     

Composition and physiological functions of the porcine colostrum

The first secretion, 24-h post parturition of the mammary glands of sows, known as colostrum, is high in protein and low in lactose and fat. As a consequence of an insufficient ingestion of colostrum, more than 50% of piglets fail to reach weaning and die. The composition and some functions of colostrum have been previously reported. For example, colostrum carbohydrates consist of mainly lactose. Lipids in the colostrum are mostly triacylglycerols, but <1% is fatty acids, which may act as homeostasis regulators. Similarly, proteins are found mostly as casein and whey, the latter being ≥80% immunoglobulins. Colostrum-derived immunoglobulins and bioactive proteins such as azurocidin help the immune system of the piglet fend off infections. In addition, leukocytes and exosomes are other minor but nonetheless equally crucial bioactive components in the porcine colostrum. Modern pig farming has achieved increases in pig productivity and litter size, but this has been accomplished in detriment of the health and the survival rate of piglets. Therefore, porcine colostrum is now even more important in pig farming. In the present review, we discuss the current knowledge on the composition and physiological functions of the porcine colostrum and briefly propose future research directions.     

非洲猪瘟的防控关键技术

非洲猪瘟传入我国以来,给我国养猪业造成了巨大的损失。非洲猪瘟可防可控,文章从消灭传染源、切断传播途径、保护易感猪群方面介绍了构建猪场生物安全体系的防控技术。