ObjectiveTo investigate the aim antigen coursing the hyperacute rejection of xenotransplantation. MethodsDocuments about hyperacute rejection in xenotransplantation were reviewed and summarized in detail. ResultsPig is thought to be one of the ideal donors of xenotransplantation, but the major obstacle is hyperacute rejection mediated by complement that is activated though human serum. αGal is recognized as the major antigen and its expression is controlled by α1,3 galactosyltransferase. Immunoabsorption of preexsisted antibody, enzymatic digestion of αGal, knockout αGT gene and transgenic technology have been used to solve this problem. Even so, there remain other antigens which can combine with natural antibodies in human serum, such as, 40×103 molecule in erythrocyte, 210×103, 105×103 and 50×103 antigen in pig embryo brain cell, etc. Conclusion αGal is the major antigen which course the hyperacute rejection. Besides αGal, many nonalphagal need further investigation.
Xenotansplantation has become a global focus because it may solve the formidable problems in allotransplantation, that is, the donor source. Hitherto clinical xenotransplantion has been in the stage of research with limited cases and unsatisfactory results. The difficulties which hinder the progress of xenotransplantation include: the ideal animal donor has not been found, it is rather difficult to control the rejections (hyperacute rejection, acute vascular rejection, perhaps acute cellular rejection and chronic rejection) after xenotransplantation compared with those after allotransplantation, some animal diseases might be transmitted to and do harm to human recipients, even the community. It is still unknown whether the functions of animal organs can substitute those of human organs permanently. Transgenic pigs on research and various measurements to suppress humoral and cellular immunity may be helpful in overcoming the problems of xenogeneic rejections. Animal diseases should be prevented, screened and treated, and animal models should be established to study the possibility of satisfactory working of animal organs in human body before clinical xenotransplantation is widely practised.
Objective To establish the swine to monkey auxiliary heterotopic liver transplantation model and to summarize surgical points. Methods Five healthy landrace piglets and five rhesus monkeys were adopted to establish the xenogenic auxiliary heterotopic liver transplantation model. In our trail landrace piglets were treated as donor andrhesus monkeys were treated as receptor. Putting the transplanted liver which included right posterior segment and part of right anterior segment into rhesus’ nest and left paracolic sulcus， and then blocking abdominal aorta and inferior vena cava shortly for end-to-side anastomosis in portal vein of transplanted liver and abdominal aorta of receptor， in infra-hepatic vena cava of transplanted liver and inferior vena cava of receptor. Ligation was performed at hepatic artery with no recon-struction. The postoperative situation and survival time of the receptors were observed. Results Four pairs of transplan-tation models were successfully established. The duration of donor liver harvesting， donor liver preparation， occlusion of recipient inferior vena cava， occlusion of abdominal aorta， and liver transplantation were （30±5） min （24-35 min），（40±10） min （31-51 min）， （30±6） min （23-36 min）， （30±8） min （22-38 min）， and （220±80） min （130-310 min）， respectively. The blood loss during transplantation was （42±6） mL （35-48 mL）. There were no thrombosis of the anas-tomosis and biliary fistula in receptors after operation， but 4 receptors died at 48， 54， 88， and 96 hours after liver transp-lantation respectively. Conclusions Swine to monkey auxiliary heterotopic liver transplantation model has b repea-tability， operation procedure is easy， and transplanted organ of it have good perfusion， which can be available for various kinds of basic and preclinical researches.
Objective To summarize the research progress on the source and selection of donor cells in the field of islet replacement therapy for diabetes mellitus. Methods Domestic and abroad literature concerning islet replacement therapy for diabetes mellitus, as well as donor source and donor selection was reviewed and analyzed thoroughly. Results The shortage of donor supply is still a major obstacle for the widely clinical application of pancreatic islet transplantation (PIT). Currently, in addition to the progress on the allogeneic/autologous donor islet supply, some remarkable achievements have been also attained in the application of xenogeneic islet (from pig donor), as well as islet like cells derived from stem cells and islet cell line, potentially enlarging the source of implantable cells. Conclusion Adequate and suitable donor cell supply is an essential prerequisite for widely clinical application of PIT therapy for type 1 diabetes mellitus (T1DM). Further perfection of organ donation system, together with development of immune-tolerance induction, gene and bioengineering technology etc. will possibly solve the problem of donor cell shortage and provide a basis for clinical application of cellular replacement therapy for T1DM.
Objective To establish a patient-derived tumor xenograft (PDTX) model and to observe the latency and rate of tumor formation, tumor size, tumor invasion and metastasis of transplanted tumors. Methods Seven patients with chest tumor in Drum Tower Hospital from April to December 2015 were chosen. There were 5 males and 2 females with age ranging from 61-71 years, including 4 patients of esophageal tumor and 3 patients of lung tumor. PDTX model was established by surgical removal of fresh tumor tissues of these patients and transplantation in NOD-Prkdcem26Il2rgem26Nju subcutaneous (NCG) mice. The latency and rate of tumor formation, tumor size, tumor invasion and metastasis of transplanted tumors were observed, and pathology of HE staining and immunohistochemical testing results were compared between PDTX model and the patients. Results PDTX model was successfully established in 4 patients, and the success rate was 66.7%, including 2 patients of esophageal cancer. The PDTX model retained the differentiation, morphological and structural characteristics of original tumors. Conclusion Pathology and molecular biology characteristics of PDTX model are consistent with the original tumor, which can be an " avatar” of tumor patients for clinical pharmacodynamics screening and new drug research and development.
ObjectiveTo explore the effect of transplanting neonatal porcine islet cells of pig via hepatic portal vein in type Ⅰ diabetic monkeys.MethodIn this study, three pig-monkey islet xenotransplantation experiments were carried out by using α-1, 3-galactosyltransferase (GGTA1) gene knockout neonatal pig islet cells.ResultsThree macaques were successfully transplanted with islet cells. After the operation, their vital signs were stable and no symptoms of venous embolism occurred. After transplantation, the blood glucose and the dosage of exogenous insulin were significantly reduced, and the specific porcine C-peptide could be detected. Three macaques developed symptoms of ketoacidosis, and one macaque developed wound infection. After symptomatic treatment, all of them survived for 16 weeks.ConclusionGGTA1 knockout neonatal porcine islet cells transplanted through hepatic portal vein is effective for the treatment of type Ⅰ diabetes.
On January 7, 2022, the University of Maryland Medical Center reported that the world’s first gene-edited pig heart was successfully transplanted into a 57-year-old man with end-stage heart disease, causing a global attention. The first gene-edited pig heart transplanted into a human successfully survived for 59 d without showing early signs of rejection, creating a history of xenotransplantation and marking a key step forward the clinical development of xenotransplantation. This article focuses on the role of gene editing in alleviating immune rejection, summarizes the case of xenotransplantation at the Maryland Medical Center, and outlines the current status of xenotransplantation and the unresolved issues of xenotransplantation. It is expected that xenotransplantation can successfully enter the clinic in the near future.
In recent years, breakthroughs in genetic engineering (GE) and cloning technology have led to the successful cultivation of “designated pathogen free (DPF) xenotransplantation (XENO) medical (M) pigs” (hereinafter referred to as GE-DPF-XENO-M pigs). Based on GE-DPF-XENO-M pigs, a large number of xenotransplantation experiments with non-human primates (NHPs) as recipients basically answered the most concerned questions: overcoming hyperacute rejection and cross species infection. These achievements directly accelerate to the emergence of a new “xenotransplantation subclinical research model”. At the end of 2021, Montgomery and Porrett teams in the United States successively transplanted GE pig kidney into the remains of 3 brain dead cases, no hyperacute rejection occurred after 48–72 hours. These three subclinical studies provide a scientific basis for xenotransplantation into clinical research. On January 7, 2022, Griffith, Maryland, USA, etc. transplanted a GE pig heart to a patient with severe heart failure and survived for 59 days. The above progress shows that xenotransplantation has taken a key step towards the stage of clinical research, which is worthy of our peers’ attention and reference.