The Relative Roles of Inflammation in Kidney Allotransplantation and Xenotransplantation.

The nature and severity of the inflammatory response influences the outcome of organ allotransplantation and xenotransplantation. In allotransplantation, the source of the allograft, for example, from a living, brain-dead, or circulatory death donor, influences the inflammatory response, as do such factors as the preexisting comorbidities and the length of the period of chronic kidney disease in the recipient and the management he/she has received. There is also inflammation associated with the transplant surgery, for example, as a result of ischemia-reperfusion injury.

Future Therapy for End-Stage Kidney Failure: Gene-Edited Pig Kidney Xenotransplantation.

In patients with end-stage kidney disease, kidney transplantation from a living or deceased human donor offers a much-improved quality and length of life. Gene-edited pigs might provide an alternative source of kidneys for clinical transplantation (xenotransplantation). The major pathobiological barriers to successful pig kidney xenotransplantation have steadily been overcome by the following methods: (1) genetic engineering of the organ-source pig and (2) the administration of novel immunosuppressive agents.

Engineering sialylation in pigs: A promising strategy for overcoming xenograft rejection and revolutionizing organ transplantation.

The organ shortage crisis leaves over 100,000 people waiting for transplants, causing 6,000 deaths annually. To address this, pigs are being explored as potential donors. Despite advances like the FDA-approved GalSafe pig, immunological challenges remain.

Pilot Survey of Attitudes Toward Xenotransplantation Among Nursing Students in London, UK.

Background: Solid organ xenotransplantation has been approved for clinical trials in the United States. Because of the role of nurses in patient decision-making, it is important to understand the attitudes of the future nursing workforce toward xenotransplantation. This pilot study aimed to investigate the attitudes of adult nursing students toward xenotransplantation.

Human CD55 Expression and C1 Inhibition Partially Protect Gene-Edited Pig Red Blood Cells From Human Complement-Mediated Hemolysis In Vitro.

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).

Impact of COVID-19 Vaccination and Infection on Anti-Triple-Knockout (TKO) Pig Antibody Production: A Study in Patients With End-Stage Liver Disease and Liver Transplant Recipients.

This study investigates the impact of COVID-19 vaccination, with a focus on inactivated vaccines, on the production of anti-triple-knockout (TKO) pig antibodies, crucial for xenotransplantation. Although it is known that vaccination influences anti-pig antibody production, the specific effects of COVID-19 vaccines, particularly inactivated forms, remain underexplored. We analyzed serum samples from healthy individuals, patients with end-stage liver disease (ESLD), and liver transplant (LT) recipients to assess antibody binding to TKO pig cells.

Contributions of Europeans to Xenotransplantation Research: 2. Pig Islet and Cell Xenotransplantation.

Pig islet xenotransplantation in nonhuman primates (NHPs) has made considerable progress during the past 30 years, and European scientists in both Europe and the USA have contributed to this progress. At times, there have been, or are, active research programs in Sweden, Germany, Belgium, and the USA. The first clinical experiments of wild-type (i.

Treatment of Presumptive Rejection After Orthotopic Pig-to-Baboon Cardiac Xenotransplantation.

Background: Significant progress has been made in the long-term survival of non-human primates after orthotopic gene-edited pig cardiac xenotransplantation. However, to our knowledge, there are no reports of the successful reversal of an acute rejection episode in such an experiment. We present evidence suggesting that rejection can be reversed with corticosteroids and complement inhibition.

International Xenotransplantation Association (IXA) Position Paper on Kidney Xenotransplantation.

Porcine kidney xenotransplantation for end-stage renal disease (ESRD) has reached the stage of clinical testing following major advances in donor pig genetic modifications and effective immunosuppressive strategies through decades of rigorous translational research. Reports of pig kidney xenograft survival beyond 1 year posttranplant in nonhuman primate (NHP) models justify optimism for its potential as an alternative to allotransplantation. In the United States, experimental transplantations of genetically engineered (GE) porcine kidneys into brain-dead subjects and a small number of ESRD patients have shown no evidence of hyperacute rejection and adequate pig kidney function for up to several months.

International Xenotransplantation Association (IXA) Position Paper on Kidney Xenotransplantation.

Porcine kidney xenotransplantation for end-stage renal disease (ESRD) has reached the stage of clinical testing following major advances in donor pig genetic modifications and effective immunosuppressive strategies through decades of rigorous translational research. Reports of pig kidney xenograft survival beyond 1 year post-transplant in nonhuman primate (NHP) models justify optimism for its potential as an alternative to allotransplantation. In the United States, experimental transplantations of genetically engineered (GE) porcine kidneys into brain-dead subjects and a small number of ESRD patients have shown no evidence of hyperacute rejection and adequate pig kidney function for up to several months.

Contributions of Europeans to Xenotransplantation Research: 1. Pig Organ Xenotransplantation.

Xenotransplantation has a rich history, marked by European pioneers who laid the groundwork for many breakthroughs in the field. Pig organ xenotransplantation offers a solution to the global shortage of deceased human donor organs, whilst allowing the modification of the donor graft itself. The field has continued to garner interest, particularly with the recent advent of simpler and faster genetic-engineering technologies.

Inhibition of inflammation by IL-6 blockade in xenotransplantation.

The inflammatory cytokine interleukin 6 (IL-6) plays a role in both acute and chronic organ allotransplant rejection. Data suggest that IL-6 inhibition may help prevent or reverse rejection, with large multi-center trials now underway. However, the evidence for the benefit of IL-6 inhibitors in xenotransplantation is limited.

How Much Will a Pig Organ Transplant Cost? A Preliminary Estimate of the Cost of Xenotransplantation Versus Allotransplantation in the USA.

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.

Xenotransplantation of a Porcine Kidney for End-Stage Kidney Disease.

Xenotransplantation offers a potential solution to the organ shortage crisis. A 62-year-old hemodialysis-dependent man with long-standing diabetes, advanced vasculopathy, and marked dialysis-access challenges received a gene-edited porcine kidney with 69 genomic edits, including deletion of three glycan antigens, inactivation of porcine endogenous retroviruses, and insertion of seven human transgenes. The xenograft functioned immediately.

Is Allosensitization Detrimental to Pig Organ Xenotransplantation, and Is Xenosensitization Detrimental to Subsequent Organ Allotransplantation? A Debate Organized by the International Xenotransplantation Association (IXA).

This report summarizes the content of a debate sponsored by eGenesis Bio, organized by the International Xenotransplantation Association (IXA), and attended by more than 150 delegates in the context of the IPITA-IXA-CTRMS Joint Congress held in San Diego in October 2023. The debate centered around two important immunological topics relating to xenotransplantation. The first was a debate relating to the statement that "HLA-sensitized patients are at higher risk for rejecting a pig xenograft.

Characterizing coagulation responses in humans and nonhuman primates following kidney xenotransplantation-A narrative review.

The recent report of the first pig kidney transplant in a living human brings hope to thousands of people with end-stage kidney failure. The scientific community views this early success with caution as kidney xenotransplantation exhibits many challenges and barriers. One of these is coagulation dysregulation.

Extended survival of 9- and 10-gene-edited pig heart xenografts with ischemia minimization and CD154 costimulation blockade-based immunosuppression.

Background: Xenotransplantation has made significant advances recently using pigs genetically engineered to remove carbohydrate antigens, either alone or with addition of various human complement, coagulation, and anti-inflammatory ''transgenes''. Here we evaluated results associated with gene-edited (GE) pig hearts transplanted in baboons using an established costimulation-based immunosuppressive regimen and a cold-perfused graft preservation technique.

Methods: Eight baboons received heterotopic abdominal heart transplants from 3-GE (GalKO.

The importance of public engagement in clinical xenotransplantation.

Over the past several decades, significant scientific progress in xenotransplantation has brought the field to the threshold of clinical trials. In the past 3 years in the United States, experimental pig kidney and heart xenotransplantation have been performed on human subjects recently declared dead by neurological criteria (decedents). In addition, two pig heart transplants have been carried out in living patients under the United States Food and Drug Administration's expanded access guidelines.

Close contacts of xenograft recipients: Ethical considerations due to risk of xenozoonosis.

With decades of pre-clinical studies culminating in the recent clinical application of xenotransplantation, it would appear timely to provide recommendations for operationalizing oversight of xenotransplantation clinical trials. Ethical issues with clinical xenotransplantation have been described for decades, largely centering on animal welfare, the risks posed to the recipient, and public health risks posed by potential spread of xenozoonosis. Much less attention has been given to considerations relating to potentially elevated risks faced by those who may care for or otherwise have close contact with xenograft recipients.

A brief review of the current status of pig islet xenotransplantation.

An estimated 1.5 million Americans suffer from Type I diabetes mellitus, and its incidence is increasing worldwide. Islet allotransplantation offers a treatment, but the availability of deceased human donor pancreases is limited.

Pediatric Cardiac Xenotransplantation: Recommendations for the Ethical Design of Clinical Trials.

For children with complex congenital heart problems, cardiac allotransplantation is sometimes the best therapeutic option. However, availability of hearts for pediatric patients is limited, resulting in a long and growing waitlist, and a high mortality rate while waiting. Cardiac xenotransplantation has been proposed as one therapeutic alternative for neonates and infants, either in lieu of allotransplantation or as a bridge until an allograft becomes available.