Xenotransplantation最新文献

The escalating incidence of heart failure globally, and in the United States, necessitates innovative solutions beyond conventional human cardiac transplantation due to donor heart shortage. Recent measures to overcome this shortage include the novel idea of cardiac xenotransplantation, with the first procedure done in January 2022 at the University of Maryland. However, the patient did not survive in the postoperative phase, highlighting potential challenges in cardiac xenotransplantation. Trace amounts of research exist on the physiological impacts subsequent to innate anatomical differences of porcine hearts, regardless of genetic modifications in growth rates. As such, this review aims to explore and address the critical implications of utilizing genetically modified porcine hearts for cardiac xenotransplantation as it pertains to postoperative physiological function. An analysis of literature discussing multiple anatomical and physiological factors, such as differences in organ dimensions, vasculature, and cardiac conduction, was carried out. Although xenotransplantation offers a promising solution, the present analysis of relevant literature points out potentially important considerations relating to long-term survivability.

Background: In recent years, gene-edited pigs have become sources of organs for clinical xenotransplantation. They have the potential to be sustainable sources of red blood cells (pRBCs). We investigated in vitro the effect of human complement inhibition by using (i) human CD55-expressing pRBCs from pigs with 10 gene-edits (10GE) and (ii) a C1-esterase inhibitor (C1-INH).

Methods: RBCs were collected from pigs (triple-knockout [TKO] with or without expression of "protective" human transgenes [10GE] on peripheral blood mononuclear cells [PBMCs], including two complement-regulatory proteins, hCD46 and hCD55). hCD46 and hCD55 expression, anti-pRBC antibody binding, and C3b/iC3b deposition were measured by flow cytometry. Hemolysis by complement-dependent cytotoxicity (CDC) was measured by a plate reader. A C1-INH was added to the hemolysis assay.

Results: HCD46 was not expressed on either TKO or 10GE pRBCs. hCD55 was expressed at low levels on 10GE pRBCs. Hemolysis induced by human complement and anti-pRBC antibodies was less when pRBCs were from 10GE pigs than from TKO pigs (57.3% ± 2.2% vs. 26.2% ± 3.8%, p < 0.01). C3b/iC3b deposition of 10GE pRBCs under nonhemolytic conditions was also lower. C1-INH decreased hemolysis (No C1-INH = 18.6% ± 2.3% vs. 2.5U/mL C1-INH = 7.0% ± 1.1%, p < 0.05). C3b/iC3b deposition on pRBCs was also decreased (gMFI: No C1-INH = 2680 ± 82 vs. 2.5 U/mL C1-INH = 719 ± 57, p < 0.01).

Conclusions: Even low expression of hCD55 contributes to the protection of pRBCs from hemolysis by CDC, but the possibility of phagocytosis still remains. However, C1-INH partially protects pRBCs from hemolysis and C3b/iC3b deposition. Therefore, higher hCD55 expression and the administration of a complement inhibitor are likely to prolong pRBC survival after clinical xenotransfusion.

Pancreatic islet transplantation stands out as a promising therapeutic avenue for type 1 diabetes patients grappling with glycemic instability and hypoglycemia unawareness. Given the persistent scarcity of donor organs, there is growing anticipation that pig-to-human islet xenotransplantation will emerge as the definitive beta cell replacement therapy for this condition. The liver is the site of preclinical pig-to-NHP islet transplantation as well as allogeneic clinical transplantation, yet its pathology following islet transplantation remains poorly understood. Based on our observations of post-transplantation periportal pathologic changes in primate models, we have conducted a retrospective study examining the hepatic pathology in pig-to-NHP islet recipients with short-term graft survival, employing a state-of-the-art spatial transcriptomic platform within the vicinity of the islet implantation site. Post-transplantation liver tissue could be easily demarcated into three transcriptionally distinct regions, consistent with its histology. A notable elevation in adipogenesis and non-alcoholic fatty liver disease (NAFLD) pathways was observed, exemplified by increased expression of SREBF1, IGF1, CEBPA, FASN, GCK, and SCD. We furthermore discovered that, despite the decreased severity of the multifocal white lesions indicated by gross examination at 33 days post-transplantation, there was still evidence of fatty liver disease at the transcriptional level. These results warrant further research into the relationship between intrahepatic islet transplantation and the hepatic microenvironment.

Introduction: Shortage of donor organs is one of the greatest challenges of cardiac transplantation. Xenotransplantation is a potential way to solve the contradiction of imbalance and pigs are considered ideal donor sources. However, xenotransplantation still faces the problem of immune rejection at present. In order to further understand the molecular picture of immune rejection after xenotransplantation, and develop immunosuppressive agents to further overcome rejection, we conducted a proteomic analysis of a heterotopic pig-to-non-human primate (NHP) animal model.

Methods: We constructed a heterotopic NHP animal model using wild-type (WT) and alpha-1,3-galactosyltransferase gene knockout (GTKO) porcine hearts as donors. Based on quantitative proteomics analysis, we investigated the changes of protein after CXTx in three groups: Group I: WT donor heart, Group II: GTKO donor heart without immunosuppression, and Group III: GTKO donor heart with immunosuppression. Finally, we assessed the efficacy of the target using a heterotopic heart transplantation model from SD rats to Balb/c mice.

Results: A total of 2425 proteins were identified in the donor heart tissues and approximately 15% of proteins were significantly changed after CXTx, most of them had increased expression. The results of proteomic analysis demonstrated that chronic hypoxia injury induced by microvascular thrombosis may play an important role during cardiac xenograft failure, confirmed by histopathological results. Remarkably, we showed some novel targets especially increased expression of pentraxin 3, MVP, and HSP90AB1 that cannot be suppressed in the present gene editing and immunosuppressive interventions. Because NF-κB is a common downstream regulator of these three proteins, we hypothesize that it may be crucial to the occurrence of xenograft failure and considered as a potential therapeutic target. Using the SD Rat-Balb/C Mouse CXTx model and inhibiting NF-κB with BAY 11-7082, we found that NF-κB targeting prolonged graft survival from 5 to 8 days and reduced myocardial inflammation.

Conclusions: In summary, the proteomic analysis could help us to solve the mystery of cardiac xenograft failure, confirm the key pathways, and reveal a clear vision of future interventions. NF-κB inhibition effectively decreased immune cell infiltration and antibody deposition in myocardial tissue, suggesting its potential as a therapeutic strategy to enhance graft survival and reduce inflammation in cardiac xenotransplantation (CXTx).

Organ failure poses a substantial global health challenge, and xenotransplantation emerges as one of the most promising avenues to mitigate the critical shortage of donor organs. In recent years, numerous research institutions have undertaken clinical and preclinical xenotransplantation in humans, instilling hope for notable progress. Nevertheless, formidable obstacles persist before success can be fully achieved. Chinese researchers have been at the forefront of xenotransplantation studies, actively contributing to several pivotal areas: the identification of critical genes essential for xenotransplantation and the creation of genetically modified pigs; preclinical studies on pig-to-nonhuman primate organ and tissue xenotransplantation, as well as the utilization of genetically engineered pig-derived biomaterials; contributions to both preclinical and clinical xenotransplantation research; and the formulation and refinement of xenotransplantation policies and ethical guidelines in China. In conclusion, this review seeks to not only acknowledge the contributions of Chinese researchers but also to encourage further collaboration between Chinese scholars and their international counterparts in advancing the field of xenotransplantation.

Background: Neonatal porcine islets (NPIs) can mature into a mixed population of endocrine cells that can restore glucose control in mice, pigs, and non-human primates, representing a potential alternative islet source for clinical beta cell replacement therapy. However, it remains unclear how conditions in the recipient influence the maturation and function of these cells. Here, we investigated the impact of host sex on NPIs implanted under the kidney capsule of male and female B6.129S7-Rag1^tm1Mom (B6/Rag^-/-) mice.

Methods: Diabetic mice were transplanted with 3000 NPIs under the kidney capsule. All mice were monitored for reversal of hyperglycemia and glucose clearance at 8- and 20-weeks post-transplant. Grafts were assessed for cell composition and insulin content.

Results: Female mice demonstrated improved glucose clearance at 8- and 20-weeks post-transplant compared to their male counterparts. Improved glucose clearance correlated with accelerated diabetes reversal in females (8 weeks vs. 12 weeks in males) and increased rates of euglycemic achievement (17/18 in females vs. 14/19 in males). However, grafts collected from male mice exhibited an increased percentage of insulin-positive cells as well as increased insulin content.

Conclusion: The sex of the host influences the outcomes of NPI transplantation, showcasing the relevance of understanding the role of sex as a biological variable in islet transplantation.

Xenotransplantation, the transplantation of organs or tissues between species, offers a promising solution to the organ donor shortage. This study examines the research landscape of the field, identifying key trends, influential studies, and leading contributors. A search of the Scopus database on June 24, 2024, focused on solid-organ xenotransplantation publications. Articles were analyzed using Vosviewer, Bibliometrix, and Microsoft Excel. The analysis included 1072 articles with 26 066 citations, reflecting substantial impact in transplantation research. The average citations per document were 24.32, with an annual publication growth rate of 7.63%. Key sources included Xenotransplantation, Transplantation, and Transplantation Proceedings. Cooper was the most influential author, and Harvard Medical School was the leading institution. The United States dominated in publication output and citations. The most cited article, by Hering et al. (2006), had 458 citations. The study highlights the significant growth and increasing attention to xenotransplantation, with ongoing trials emphasizing its potential. This analysis provides insights into the field's progress and serves as a guide for future translational research to advance xenotransplantation toward clinical application.

Background: As xenotransplantation advances toward clinical trials, viewpoints from various segments of society are continually needed to engage the public and to inform the prospective clinical trials. As the majority of the world's population identifies with a religious tradition, religious perspectives regarding the ethical issues associated with clinical xenotransplantation are an important element to take into account.

Methods: At the 2024 Congress of The Transplantation Society in Istanbul, Türkiye, a group of religious scholars from Catholicism, The Church of Jesus Christ of Latter-day Saints, Hinduism, Shia Islam, Judaism, Protestant Christianity, and the African American religious traditions met together to discuss viewpoints toward xenotransplantation from their respective religious tradition. Additional contributions were received from representatives from the American Anglican Episcopal Church and Sunni Islam faith traditions.

Results: Each speaker presented viewpoints on the ethical issues associated with clinical xenotransplantation from their own religious perspective. Common issues that were raised include the treatment and stewardship of animals, xenozoonotic infection and other risks, while religious dictums of particular relevance for each faith tradition were noted.

Conclusion: Overall, none of the participants considered xenotransplantation to be impermissible within their religious tradition. Yet, it is important to note that persons of religious faith may come to different conclusions from their coreligionists about the permissibility of xenotransplantation as a personal choice or as spokespersons for others of their faith. Additional empirical viewpoint data from each religious tradition will be helpful to further inform normative views and measure the impact of public education. As xenotransplantation continues to advance to the clinic, continued exploration of religious perspectives is needed to best support individual decision-making and optimize patient-centered care.

Background: Surgical bleeding is a risk in any solid organ transplant, and is commonly addressed with the transfusion of human blood products to replace or supplement coagulation factors. It is unknown if these blood products would harm xenotransplanted pig organs in human recipients demonstrating coagulopathy. The aim of this study was to investigate in vitro if blood products such as fresh frozen plasma (FFP) or cryoprecipitate (cryo) contain xenoantibodies capable of cytotoxicity to GTKO pig cells.

Methods: We obtained 12 individual single-donor (7 FFP and 5 cryo) blood products from our institution's blood bank for testing. Peripheral blood mononuclear cells (PBMCs) were obtained from a GTKO/hCD55 pig for use as target cells. We performed a series of flow cytometry crossmatch (FCXM) and complement-dependent cytotoxicity (CDC) assays.

Results: We found that all the tested blood products contained some degree of IgM and IgG xenoantibody. Tests using a 1:50 dilution revealed a significant decrease in IgM xenoantibody binding, but an increase in the detection of IgG binding. Multiple preparations were capable of GTKO PBMC cytotoxicity but the level of antibody binding and cell death varied by preparation.

Conclusions: Both FFP and cryo contain IgM and IgG non-galactose-α-1,3-galactose (αGal) xenoantibodies capable of killing GTKO PBMCs, though the level varies by preparation. Although some centers utilize a genetic background with mutations in the three enzymes responsible for the known xenoantigens, others are investigating the GTKO pig as a potential option. These results suggest that a center pursuing a human xenotransplantation study with a GTKO genetic background should pre-screen blood products prior to administration.