Xenotransplantation最新文献

Religious viewpoints have been shown to influence the ways in which many persons approach medical decision-making and have been noted as a potential barrier to xenotransplantation acceptance. This study sought to explore how attitudes toward xenotransplantation differ among various religious beliefs. A national Likert-scale survey was conducted in 2023 with a representative sample in the United States. Religious belief was self-reported. Regression analysis was used to identify associations with religious belief and hesitations about xenotransplantation. Five thousand and eight individuals across the United States responded to the survey. The two biggest concerns about xenotransplantation across religious groups were the current lack of evidence about success and the risk of xenozoonosis. Although they still expressed concerns about certain issues, Catholic and Muslim respondents were most comfortable with xenotransplantation for all. On average, the risk of xenozoonosis was a concern among 25% across all religious beliefs (p <0.0001). Orthodox Christians expressed the highest rate of negative feelings toward the recent xenotransplantation experiments on brain dead and living individuals. Those who reported no religion were most likely to have negative feelings about killing pigs for human organ transplant (OR 1.26; 95% CI: 1.08-1.46). As xenotransplantation progresses from pre-clinical studies to clinical trials, and potentially to clinical therapy, hesitations among religious groups exist. Specific studies should be designed to investigate how religious viewpoints can affect xenotransplantation acceptance.

Introduction: There is no standard protocol for management of organ preservation for orthotopic, life-sustaining cardiac xenotransplantation, particularly for hearts from pediatric sized donors. Standard techniques and solutions successful in human allotransplantation are not viable. We theorized that a solution commonly used in reparative cardiac surgery in human children would suffice by exploiting the advantages inherent to xenotransplantation, namely the ability to reduce organ ischemic times by co-locating the donor and recipient.

Methods: Orthotopic cardiac xenotransplantation was performed from genetically engineered pigs to size matched baboons. A dose of modified Del Nido cardioplegia initiated donor heart arrest and was followed by a second dose mixed with recipient blood prior to implant. Hemodynamics and cardiac function were tracked with a combination of invasive and non-invasive measures.

Results: Mean ischemic time and cardiopulmonary bypass times were 54.1 ± 14.6 and 84.1 ± 14 min respectively. The ejection fraction following chest closure was preserved at >50% for all animals. This finding persisted at 48hours. Mean inotropic score at 24 h post-implant was 9.7 ± 3.

Conclusion: Del Nido cardioplegia solution when combined with short graft ischemic times demonstrates promising outcomes to avoid primary graft dysfunction for cardiac xenografts in a small animal model of life-sustaining orthotopic cardiac xenotransplantation. Ex vivo perfusion systems may be unnecessary for successful clinical implementation of this evolving technology.

Background: The removal of preformed antibodies with cleaving enzymes like IdeS (imlifidase) has demonstrated therapeutic potential in organ transplantation for sensitized recipients. However, preformed xenoreactive antibodies (XAbs) against porcine glycans are predominantly IgM and considered detrimental in pig-to-human xenotransplantation.

Methods: Recombinant IceM, an endopeptidase cleaving IgM, was generated in Escherichia coli (E. coli). Four maximally MHC-mismatched rhesus macaques underwent two serial skin transplantations to model allosensitized patients awaiting xenotransplantation. IceM was administered IV in allosensitized animals at 28 and 56 days after the first skin transplantation to assess in vivo IgM cleavage. Total IgG and IgM were quantified with western blot, and anti-pig (xenoreactive) IgG/IgM were evaluated using flow crossmatch. B cells and their subpopulations were assessed using flow cytometry.

Results: IceM selectively cleaved human IgM, while showing no cleavage activity toward other isotypes, including IgG, IgA, IgD, and IgE. Additionally, IceM cleaves only human and nonhuman primate IgM in vitro, but not in sera from other species. At a dose of 0.5 mg/kg, IceM reduced xenoreactive IgM levels to 13.76% ± 4.98% of baseline (B cell flow crossmatch) at 24 h postadministration, with baseline levels restored approximately 2 weeks after treatment. Additionally, animals showed similar kinetics of xenoreactive IgM degradation with the repeated dose of IceM.

Conclusion: In this study, we report a recombinant bacterial enzyme that selectively cleaves IgM in human and nonhuman primate sera. Repeat administration of IceM in macaques enables selective, robust clearance of circulating xenoreactive IgM. This approach will be useful in treating preformed natural and rebound IgM in xenotransplantation.

Organ transplants are used to treat many end-stage diseases, but a shortage of donors means many patients cannot be treated. Xenogeneic organs have become an important part of filling the donor gap. Many current studies of kidney, heart, and liver xenotransplantation have used gene-edited pig organs on brain-dead recipients. However, the endocrine system, immune system, and nervous system of brain-dead people are changed, which are different from that of real patients transplanted, and the current research results of brain death (BD) recipients are also different. So there are drawbacks to using brain-dead people for xenotransplantation. In addition, although the policy requires the use of non-human primate (NHP) experiments as the research standard for xenotransplantation, there are still differences between NHP and humans in terms of immunity. Therefore, to better study xenotransplantation, new models may be needed in addition to NHP and brain-dead individuals. Humanized animal models or organoids may be able to fill this gap.

Background: CD40-CD154 pathway inhibitors are considered indispensable immunosuppressive drugs in xenotransplantation. At present, novel anti-CD154 and anti-CD40 monoclonal antibodies (mAbs) are continuously being developed. It is important to establish a simple and efficient in vitro method to evaluate the effectiveness of these therapeutic mAbs.

Methods: A modified CD40L-activated B-cell proliferation model was established using irradiated NIH/3T3 cells transfected with human CD40 ligand (hCD40L-NIH/3T3) as stimulator cells and human or rhesus monkey peripheral blood mononuclear cells (PBMCs) as responder cells. After 8 days of culture, B-cell proliferation was detected by flow cytometry. Various concentrations of anti-CD40 or anti-CD154 mAbs were added to the co-culture system as an intervention. The inhibitory effects of anti-CD154 and anti-CD40 mAbs on the proliferation of B cells from humans and rhesus monkeys were studied and compared.

Results: After 8 days of co-culture, the proliferation rate of B cells in both human and rhesus monkey PBMCs was more than 80%, and the expression of MHC-II and the co-stimulatory molecules CD80, CD86, and CD40 on B cells was significantly up-regulated. All three anti-CD154 mAbs showed a similar strong inhibitory effect on human B-cell proliferation, but the inhibitory effect on the proliferation of rhesus monkey B cells was weaker than that on human B cells, which showed a typical dose-dependent inhibition. The three anti-CD40 mAbs from different sources had different effects. One mAbs potently inhibited both human and monkey B-cell proliferation, whereas the other two mAbs exhibited strong or moderate inhibitory effects on human B-cell proliferation but had little inhibitory effect on monkey B-cell proliferation.

Conclusion: We have successfully established a modified CD40L-activated B-cell proliferation model for the in vitro evaluation of CD40-CD154 pathway inhibitors, which may provide important evidence for the selection of appropriate therapeutic antibodies and their dose determination for xenotransplantation.

Background: The global demand for organ transplantation outpaces supply, necessitating innovative solutions. Xenotransplantation, using animal organs, cells, and tissues, is a promising solution to address the organ shortage. The World Health Organization and the International Xenotransplantation Association collaboratively established an online inventory in 2006 (www.humanxenotransplant.org) to catalog human xenotransplantation practices. The inventory, managed successively by the Geneva University Hospital and the Sichuan Provincial People's Hospital, aligns with the WHO directives for transparency and best practices in the field of transplantation.

Methods: Relevant data have been regularly collected from numerous sources (scientific publications, congresses, press articles, declarations of International Xenotransplantation Association members) by a dedicated team in Switzerland and China ensuring rigorous verification. The initial information is used to create a first entry in the database which is then completed when more details become available.

Results: As of May 2024, the inventory contained 54 entries of distinct xenotransplantation procedures undertaken on humans. From these data, various trends can be observed over the last two decades regarding the type of transplantation, their regulation status, and the source animal. Notably, recent high-profile cases of solid organ transplantation involving kidneys and hearts were made feasible through years of progressive xenotransplantation research and ongoing changes to regulations.

Conclusions: Recent clinical applications of solid organ xenotransplantation suggests that more clinical procedures may soon follow for patients with end-stage kidney or heart disease, or diabetes. Future perspectives advocate for increased funding and expansion of the current registry or its potential integration into a larger and more broadly internationally recognized registry, such as the Global Observatory on Donation and Transplantation (GODT).

We reviewed the costs of organ allotransplantation and attempted to estimate the potential costs of xenotransplantation (based on the premise that, when clinically established, the results of pig organ xenotransplantation would be at least equal to those of allotransplantation). The care of patients with end-stage organ failure waiting for an allograft is expensive, particularly if chronic dialysis or mechanical support is required. Xenotransplantation has the potential to eliminate wait times for organ transplants, significantly reduce certain management costs, for example, chronic dialysis, and enable early transplantation before comorbidities develop or increase. The cost of the surgical procurement of a pig organ and its transplantation will be similar to that of allotransplantation, as will the cost of immunosuppressive therapy. The major "unknown" is the cost of purchasing a gene-edited pig organ, which is likely to be considerable. We conclude that there will be significant cost savings for the pretransplant care of an individual patient, but these may be offset by the cost of the gene-edited pig organ. However, the ready availability of an unlimited organ supply will greatly increase the number of transplants carried out each year, thus increasing the overall expenditure on transplantation.

Introduction: Although there is a plethora of literature on electrocardiographic changes following cardiac allotransplantation, there is little in the field of cardiac xenotransplantation. The only published literature to date is that of the first pig-to-human cardiac xenotransplantation. Here we take a close look at the electrocardiographic parameters in four non-human primate recipients of orthotopic cardiac xenotransplantation to develop baseline metrics for comparison.

Methods: Orthotopic cardiac xenotransplantion was carried out in four non-human primate recipients. Electrocardiographic parameters were followed at various intervals using an internal hemodynamic monitoring system (DSI) as well as a standard 12-lead electrocardiogram (ECG). ECG intervals were then compared to published literature on porcine ECG intervals and pig-to-human cardiac xenotransplantation.

Results: There were no significant differences observed between timepoints for HR, PR, QRS, QT, or QTc after cardiac xenotransplantation for each animal subject. ECG parameters were statistically similar to those of in situ mini-pig hearts in the literature. ECG parameters from the DSI on average were shorter than those from a traditional ECG, however, DSI parameters were consistent over time.

Conclusion: These results demonstrate the possibility of conduction health for genetically engineered porcine donor hearts following cardiac xenotransplantation. Ongoing work to compare the results of an ECG in a porcine donor heart before and after implantation into a NHP is necessary to better characterize variables that may be at play in the function of the conduction system.

Background: The Federal Ethics Committee on Non-Human Biotechnology (ECNH) of Switzerland is an independent expert committee appointed by the Federal Council and mandated to advise the federal authorities from an ethical perspective in the field of nonhuman biotechnology and gene technology. Due to recent developments in the field of xenotransplantation after the introduction of genome editing technologies, the ECNH has commissioned an expert report on the ethical questions of xenotransplantation with a focus on animal ethics. The subject of the inquiry is, in particular, if current developments in the field of xenotransplantation raise new questions regarding ethics in the nonhuman realm or if existing questions have to be re-examined and answered anew.

Methods: An interdisciplinary approach was applied to answer this question. Based on the latest empirical results from medicine and biotechnology, xenotransplantation is analyzed and evaluated with reference to the dignity of the creature (Würde der Kreatur)-which is defined in the Swiss Federal Constitution-and the dignity of animals (Tierwürde) that is stipulated in the Swiss Animal Welfare Act and the Federal Act on Non-Human Gene Technology, as well as contemporary positions in the ethics of the human-animal relationship.

Results: The report concludes that genome editing for xenotransplantation does not generate any qualitatively new ethical issues concerning ethics in the nonhuman realm. However, contemporary biotechnological developments must be taken as an opportunity to discuss existing ethical issues in an urgent and intensified manner, particularly regarding the significance of animals' moral standing. The lack of consideration of animal-related aspects and the neglect of current developments and the state of the art of animal ethics in the recent discussion about xenotransplantation is a scientific, ethical, and political issue because animals are most negatively affected by xenotransplantation. This is especially relevant because the contemporary state of the art in animal ethics tends to consider and protect animals more strongly than in the past.