The role of genetically engineered pigs in xenotransplantation research

Abstract

There is a critical shortage in the number of deceased human organs that become available for the purposes of clinical transplantation. This problem might be resolved by the transplantation of organs from pigs genetically engineered to protect them from the human immune response. The pathobiological barriers to successful pig organ transplantation in primates include activation of the innate and adaptive immune systems, coagulation dysregulation and inflammation. Genetic engineering of the pig as an organ source has increased the survival of the transplanted pig heart, kidney, islet and corneal graft in non-human primates (NHPs) from minutes to months or occasionally years. Genetic engineering may also contribute to any physiological barriers that might be identified, as well as to reducing the risks of transfer of a potentially infectious micro-organism with the organ. There are now an estimated 40 or more genetic alterations that have been carried out in pigs, with some pigs expressing five or six manipulations. With the new technology now available, it will become increasingly common for a pig to express even more genetic manipulations, and these could be tested in the pig-to-NHP models to assess their efficacy and benefit. It is therefore likely that clinical trials of pig kidney, heart and islet transplantation will become feasible in the near future.

Keywords: genetically-engineered; islets; non-human primate; organs; pig; xenotransplantation.

Figure 1

Macroscopic appearance of a wild-type pig kidney immediately after transplantation and reperfusion in a baboon (A) and 10 minutes later when hyperacute rejection had occurred (B).

Figure 2

Histopathology of hyperacute rejection in a wild-type pig heart graft. Complement-mediated injury associated with the binding of baboon natural preformed anti-pig antibodies to antigens expressed on the vascular endothelium of the pig organ results in intravascular thrombosis and interstitial haemorrhage. Acute humoral xenograft rejection, a delayed antibody-mediated response, is often, but not always, associated with the production of elicited antibodies, and has a similar histopathological appearance but possibly with the presence of rather more innate immune cells, such as macrophages and neutrophils. Reproduced with permission from Byrne GW, et al. Xenotransplantation 2013;20:292–307 (AQ : ensure that this reference is cited in sequence in the References list and the correct citation [number] used in this legend.)

Figure 3

Thrombotic microangiopathy in a GTKO pig heart graft. Occlusion of small vessels by fibrin deposition and platelet aggregation results in ischemic injury with replacement fibrosis.