Generally, xenotransplantation refers to any procedure that involves the transplantation, implantation, or infusion of living cells, tissues, and organs from one species to another (particularly from a non-human animal source to a human). With a high number of patients who are experiencing end-stage organ failure comes a huge demand for human organs (e.g., heart, kidney, etc.) but unfortunately, there are not enough sources or donors to fill the need.
Based on the data of the US Government Information on Organ Donation and Transplantation, there are more than 107, 000 people (adults and children) on the national transplant waiting list as of February 2021, while only 39,000 transplants were performed in 2020. Sadly, one person is added to the list every 9 minutes, while 17 people die each day while waiting for an organ transplant.
Xenotransplantation is not an entirely new concept. In fact, trials involving organs of non-human primates (NHPs) were conducted from the 1920s to the 1990s. However, the use of NHPs was banned due to several reasons, which includes:
- Differences in organ size between organ donors and recipients
- Difficulties in breeding the source animals
- High risk of transmission of infections between species
- Ethical concerns and other impracticalities
As the NHPs were taken out of the equation, researchers started using pigs as source animals. Several reasons contributed to this decision, which includes the following:
- Large litter size and early maturation period
- Organs are of comparable size and functions to humans
- Low risk of xenozoonosis (transmission of infectious diseases from animals to humans resulting from organ transplantation)
- Availability of genetic engineering techniques to produce infection-resistant organs
However, the great genetic difference between humans and porcine remains to be a huge hurdle. When the immune system detects that a non-human organ is introduced to the body, it will attack and ultimately destroy the transplanted organ. While porcine grafts have been successfully used in clinical settings, cellular and vascularized organ transplants are rejected after xenotransplantation.
Immunological Rejection and How to Avoid It
There are three main types of immunological rejection: hyperacute rejection, acute humoral xenograft rejection, and acute cellular rejection.
Hyperacute Rejection (HAR)
In hyperacute xenograft rejection, the graft is destroyed when the preformed antibodies bind to the xenoantigenic isotopes on the surface of the donor endothelial cells. This activates the complement proteins which may further damage the graft vasculature and cause graft failure. HAR is generally characterized by hemorrhage, edema, thrombosis, and loss of vascular integrity, which lead to tissue ischemia and necrosis.
This type of immunological rejection can be prevented by exhausting the pig antibodies or inhibiting the activation of the complement proteins through plasmapheresis.
Acute Humoral Xenograft Rejection (AHXR)
Also known as acute or delayed xenograft rejection, AHXR can cause xenograft rejection within days or months, even if the donor has been genetically modified to evade being detected by the immune system as of non-human origin. Severe AHXR is usually characterized by massive interstitial bleeding, infarction, thrombosis, necrosis, and loss of tubules.
Although several factors contribute to the pathogenesis of AHXR, experts believe that it is primarily triggered by preformed and induced antibodies, particularly non-Gal antigens (i.e. N-glycolylneuraminic acid (Neu5Gc) and the SDa blood group).
Acute Cellular Rejection
Like AHXR, cellular xenograft rejection may occur within days or weeks after the procedure but unlike HAR and AXHR, it is relevant to cellular and whole organ grafts. Also, this type of rejection is mediated by natural killer (NK) cells, macrophages, and T-cells.
Transgenic pigs that express specific human proteins can be the key to overcoming organ rejection. By using genetically modified pigs for xenotransplantation, the molecular differences and incompatibilities between species can finally be resolved and hopefully, there will be enough supply of human organs necessary for treating end-stage organ failure in the near future.
