Transplanting organs from pigs to humans

Abstract

The success of organ transplantation is limited by the complications of immunosuppression, by chronic rejection, and by the insufficient organ supply, and thousands of patients die every year while waiting for a transplant. With recent progress in xenotransplantation permitting porcine organ graft survival of months or even years in nonhuman primates, there is renewed interest in its potential to alleviate the organ shortage. Many of these advances are the result of our heightened capacity to modify pigs genetically, particularly with the development of CRISPR-Cas9–based gene editing methodologies. Although this approach allows the engineering of pig organs that are less prone to rejection, the clinical application of xenotransplantation will require the ability to avoid the ravages of a multifaceted attack on the immune system while preserving the capacity to protect both the recipient and the graft from infectious microorganisms. In this review, we will discuss the potential and limitations of these modifications and how the engineering of the graft can be leveraged to alter the host immune response so that all types of immune attack are avoided.

Selective germline genome edited pigs and their long immune tolerance in Non Human Primates

“…Various NHP studies have shown that the deletion of these xenoantigens in pig organs can extend graft survival in NHP (7). Studies have also reported that the additional expression of certain human transgenic proteins may be beneficial for xenografts from pig to human, such as human complement-regulatory proteins (hCRPs) (CD46, CD55, CD59), human coagulation-regulatory proteins thrombomodulin (THBD), tissue factor pathway inhibitor (TFPI), CD39, CD47and HLA-E (7, 15). The generation of multi-gene modified pigs with xenoantigen deletions and human protein expression is a major scientific advancement.With such kind of the pig, it is likely that heart, kidney and pancreatic islets xenotransplantation clinical trials would be launched in the near future (7, 15).…”

Immunogenetics of xenotransplantation

“…In addition, B cells can also present antigens to T cells and are capable of releasing cytokines thereby modulating immune cell responses towards the xenograft. B‐cell responses may be decreased by suitable T‐cell immunosuppression or tolerance induction, albeit some responses may be T‐cell independent (Chong et al., 1996; Sykes & Sachs, 2019). Similar to B cells, T cells are components of the adaptive immune system with a crucial role on xenograft rejection/survival.…”

“…This group suggests that knocking out GT and CMAH genes on porcine livers may avoid loss of platelets from circulation and prevent thrombocytopenia (Butler et al., 2016). Still, GTKO and CMAHKO pigs were not sufficient to achieve prolonged graft survival (Sykes & Sachs, 2019).…”

Development of a TaqMan Based Real-Time Fluorescent Quantitative PCR Assay for Detection of Porcine Cytomegalovirus in Semen

“…Xenotransplantation was proposed to alleviate the current shortage in human donor organs available for allotransplantation [1,2]. However, xenotransplantation may be associated with the transmission of porcine zoonotic microorganisms, including porcine endogenous retroviruses (PERVs), porcine cytomegalovirus (PCMV), porcine hepatitis E virus (HEV), and other porcine lymphotropic herpesviruses (PLHV, containing PLHV-1, PLHV-2, and PLHV-3) [3][4][5].…”