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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." Stuart Knechtle provided evidence to support this statement and Massimo Mangiola opposed it. Before the debate, a majority (>80%) of the audience agreed with this statement. After listening to the debate, this percentage was reduced to approximately 60%. The second debated statement was "Recipients of pig xenografts who develop anti‐pig antibodies are at higher risk for rejecting a subsequent allograft." This was proposed by A. Joseph Tector and opposed by Léo H. Bühler. Before the debate, once again a majority of the audience (approximately 60%) believed that prior sensitization to a pig xenograft would be detrimental to the survival of a subsequent allograft. However, after listening to the debate, only about 40% believed this statement to be correct. The topics discussed remain complex and answers are not yet conclusive. However, the present evidence suggests that allosensitization may prove detrimental to subsequent xenotransplantation, whilst sensitization to pig antigens may not be detrimental to subsequent allotransplantation. [ABSTRACT FROM AUTHOR]

The article "Hendrik Jan (Henk) Schuurman, MSc, PhD (1950–2024): In Memoriam" pays tribute to the late Henk Schuurman, a prominent figure in the field of xenotransplantation. Henk's career spanned several decades, during which he made significant contributions to the development of xenotransplantation, working with various organizations and companies worldwide. His expertise and dedication to the field were widely recognized, and his legacy continues to influence research in xenotransplantation globally. [Extracted from the article]

Antibody‐mediated rejection (AMR) is a common cause of graft failure after pig‐to‐nonhuman primate organ transplantation, even when the graft is from a pig with multiple genetic modifications. The specific factors that initiate AMR are often uncertain. We report two cases of pig kidney transplantation into immunosuppressed baboons in which we identify novel factors associated with the initiation of AMR. In the first, membranous nephropathy was the initiating factor that was then associated with the apparent loss of the therapeutic anti‐CD154 monoclonal antibody in the urine when severe proteinuria was present. This observation suggests that proteinuria may be associated with the loss of any therapeutic monoclonal antibody, for example, anti‐CD154 or eculizumab, in the urine, resulting in xenograft rejection. In the second case, the sequence of events and histopathology tentatively suggested that pyelonephritis may have initiated acute‐onset AMR. The association of a urinary infection with graft rejection has been well‐documented in ABO‐incompatible kidney allotransplantation based on the expression of an antigen on the invading microorganism shared with the kidney graft, generating an immune response to the graft. To our knowledge, these potential initiating factors of AMR in pig xenografts have not been highlighted previously. [ABSTRACT FROM AUTHOR]

Background: Xenoantigens other than Gal, Neu5Gc, and Sda may be playing a role in pig graft rejection. We investigated the incidence of antibodies to unknown pig xenoantigen in different human groups. Methods: We collected blood from TKO/hCD55 pigs (n = 3), and isolated PBMCs and RBCs. Serum samples were collected from (i) healthy human volunteers (n = 43), (ii) patients with end‐stage renal disease (ESRD) (n = 87), (iii) the same patients after kidney allotransplantation (n = 50), and (iv) renal allotransplant recipients experiencing T cell‐mediated rejection (allo‐TCMR, n = 10). The sera were initially incubated with TKO/hCD55 pRBCs (1 × 108 cells) for 1 h to absorb anti‐pig antibodies (except against SLA and possibly other antigens not expressed on pRBCs) and then the serum (absorbed or unabsorbed) was tested for antibody binding and complement‐dependent cytotoxicity (CDC) to TKO/hCD55 pig PBMCs. Results: A significant reduction in IgM/IgG binding and CDC was observed in the absorbed sera. Serum obtained before and after renal allotransplantation showed no significant difference in IgM or IgG binding to, or in CDC of, TKO/hCD55 pig cells. IgM antibodies (but rarely IgG) against unknown xenoantigens expressed on TKO/hCD55 PBMCs, possibly against swine leukocyte antigens, were documented in healthy humans, patients with ESRD, and those with renal allografts undergoing acute T cell rejection. IgM (but not CDC) was higher in patients experiencing allo‐TCMR. Conclusion: Human sera contain IgM antibodies against unknown pig xenoantigens expressed on TKO/hCD55 pPBMCs. Although not confirmed in the present study, the targets for these antibodies may include swine leukocyte antigens. [ABSTRACT FROM AUTHOR]

Clinical pig heart transplant experiments have been undertaken, and further clinical experiments and/or clinical trials of gene‐edited pig organ xenotransplantation are anticipated. The ethical issues relating to xenotransplantation have been discussed for decades but with little resolution. Consideration of certain ethical issues is more urgent than others, and the need to attain consensus is important. These issues include: (i) patient selection criteria for expanded access and/or clinical trials; (ii) appropriate protection of the patient from xenozoonoses, that is, infections caused by pig microorganisms transferred with the organ graft, (iii) minimization of the risk of a xenozoonosis to bystanders, and (iv) the need for additional public perception studies. We discuss why it is important and urgent to achieve consensus on these ethical issues prior to carrying out further expanded access experiments or initiating formal clinical trials. The ways forward on each issue are proposed. [ABSTRACT FROM AUTHOR]

This article is a tribute to Sir Roy Calne, a pioneer in the field of organ transplantation. Born in the UK to Jewish parents, Calne developed an interest in transplantation while caring for a young man with kidney failure during his medical studies. He conducted groundbreaking research on immunosuppressive drugs and carried out successful kidney transplants in dogs. Calne also briefly explored xenotransplantation, but ultimately decided that the time was not right for transplants from animals to humans. He went on to establish a successful kidney transplant program at the University of Cambridge and made significant contributions to the field of transplantation. Calne received numerous awards and honors for his work, including being knighted by the Queen. [Extracted from the article]

Half a million patients in the USA alone require treatment for burns annually. Following an extensive burn, it may not be possible to provide sufficient autografts in a single setting. Genetic manipulations (GM) of pigs offer the possibility of reducing primate humoral and cellular rejection of pig skin xenografts and thus extending graft survival. We compared the survival of skin grafts from pigs with 9‐GM with that of autografts and allografts in squirrel monkeys. Monitoring for rejection was by (1) macroscopic examination, (2) histopathological examination of skin biopsies, and (3) measurement of anti‐monkey and anti‐pig IgM and IgG antibodies. Autografts (n = 5) survived throughout the 28 days of follow‐up without histopathological features of rejection. Median survival of allografts (n = 6) was 14 days and of pig xenografts (n = 12) 21 days. Allotransplantation was associated with an increase in anti‐monkey IgM, but the anticipated subsequent rise in IgG had not yet occurred at the time of euthanasia. Pig grafts were associated with increases in anti‐pig IgM and IgG. In all cases, histopathologic features of rejection were similar. 9‐GM pig skin xenografts survive at least as long as monkey skin allografts (and trended to survive longer), suggesting that they are a realistic clinical option for the temporary treatment of burns. Although monkeys with pig skin grafts developed anti‐pig IgM and IgG antibodies, these did not cross‐react with monkey antigens, indicating that a primary 9‐GM pig skin graft would not be detrimental to a subsequent monkey skin allograft. [ABSTRACT FROM AUTHOR]