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.

Figure 1:

The growing allogeneic organ supply/demand imbalance has resulted in an expanding transplant waiting list.

Figure 2:

Schematic timeline showing advances in overcoming the immunologic challenges to xenograft survival and the impact on pig organ survival times in primates.

Figure 3:

Genetic modifications that have been made in pigs to facilitate pig to human organ transplantation. See text for details.

Figure 4:

A. Schematic of a thymokidney transplant from a pig to a baboon. B. Long-term survival of a GalT KO miniature swine thymokidney graft in a baboon with tapering immunosuppression. Serum creatinine was normal for >6 months and the graft grew markedly and was lost to cortical necrosis with no evidence of rejection at Day 193 post-transplant. Reprinted with permission from American Journal of Transplantation, 2017, 17:1778–1790.