Immunologic barriers As of 20 September 2025, no xenotransplantation trials have been successful for more than 238 days due to the many obstacles arising from the response of the recipient's
immune system, although at least two patients have not yet rejected their xenotransplants and are still off dialysis. This response, which is generally more extreme than in allotransplantations, ultimately results in rejection of the xenograft, and can in some cases result in the immediate death of the recipient. There are several types of rejection organ xenografts are faced with, these include hyperacute rejection, acute vascular rejection, cellular rejection, and chronic rejection. A rapid, violent, and hyperacute response comes as a result of
antibodies present in the host organism. These antibodies are known as xenoreactive natural antibodies (XNAs). Most non-primates contain this enzyme thus, this epitope is present on the organ epithelium and is perceived as a foreign
antigen by primates, which lack the galactosyl transferase enzyme. In pig to primate xenotransplantation, XNAs recognize porcine glycoproteins of the integrin family.
Overcoming hyperacute rejection Since hyperacute rejection presents such a barrier to the success of xenografts, several strategies to overcome it are under investigation:
Interruption of the complement cascade • The recipient's complement cascade can be inhibited through the use of cobra venom factor (which depletes
C3), soluble complement receptor type 1, anti-
C5 antibodies, or
C1 inhibitor (C1-INH). Disadvantages of this approach include the toxicity of cobra venom factor, and most importantly these treatments would deprive the individual of a functional complement system. • Increased expression of H-transferase (
α-1,2-fucosyltransferase), an enzyme that competes with galactosyl transferase. Experiments have shown this reduces α-Gal expression by 70%. • Expression of human complement regulators (
CD55,
CD46, and
CD59) to inhibit the complement cascade. • Plasmaphoresis, on humans to remove 1,3 galactosyltransferase, reduces the risk of activation of effector cells such as CTL (CD8 T cells), complement pathway activation and delayed type hypersensitivity (DTH).
Acute vascular rejection Also known as delayed xenoactive rejection, this type of rejection occurs in discordant xenografts within 2 to 3 days, if hyperacute rejection is prevented. The process is much more complex than hyperacute rejection and is currently not completely understood. Acute vascular rejection requires de novo protein synthesis and is driven by interactions between the graft endothelial cells and host antibodies, macrophages, and platelets. The response is characterized by an inflammatory infiltrate of mostly
macrophages and
natural killer cells (with small numbers of
T cells), intravascular thrombosis, and fibrinoid necrosis of vessel walls. when the complement cascade is interrupted, circulating antibodies are removed, their function is changed, or there is a change in the expression of surface antigens on the graft. This allows the xenograft to up-regulate and express protective genes, which aid in resistance to injury, such as
heme oxygenase-1 (an enzyme that catalyzes the degradation of heme). The strength of cellular rejection in xenografts remains uncertain, however, it is expected to be stronger than in allografts due to differences in peptides among different animals. This leads to more antigens potentially recognized as foreign, thus eliciting a greater indirect xenogenic response. Donor stem cells are introduced into the bone marrow of the recipient, where they coexist with the recipient's stem cells. The bone marrow stem cells give rise to cells of all hematopoietic lineages, through the process of
hematopoiesis. Lymphoid progenitor cells are created by this process and move to the thymus where negative selection eliminates T cells found to be reactive to self. The existence of donor stem cells in the recipient's bone marrow causes donor reactive T cells to be considered self-reactive and undergo
apoptosis.
Dysregulated coagulation Successful efforts have been made to create knockout mice without α1,3GT; the resulting reduction in the highly immunogenic αGal epitope has resulted in the reduction of the occurrence of hyperacute rejection, but has not eliminated other barriers to xenotransplantation such as dysregulated coagulation, also known as
coagulopathy. Different organ xenotransplants result in different responses in clotting. For example, kidney transplants result in a higher degree of
coagulopathy, or impaired clotting, than cardiac transplants, whereas liver xenografts result in severe
thrombocytopenia, causing recipient death within a few days due to bleeding. Additionally, spontaneous platelet accumulation may be caused by contact with pig von Willebrand factor. Xenotransplantation may increase the chance of disease transmission for 3 reasons: (1) implantation breaches the physical barrier that normally helps to prevent disease transmission, (2) the recipient of the transplant will be severely immunosuppressed, and (3) human complement regulators (CD46, CD55, and CD59) expressed in transgenic pigs have been shown to serve as virus receptors, and may also help to protect viruses from attack by the complement system. Examples of viruses carried by pigs include porcine
herpesvirus,
rotavirus,
parvovirus, and
circovirus. Porcine herpesviruses and rotaviruses can be eliminated from the donor pool by screening, however others (such as parvovirus and circovirus) may contaminate food and footwear then re-infect the herd. Thus, pigs to be used as organ donors must be housed under strict regulations and screened regularly for microbes and pathogens. Unknown viruses, as well as those not harmful in the animal, may also pose risks. Since then PERVs have been eliminated from the pig genomes in successfully donated pig kidneys. This was repealed in 2009 after an NHMRC review stated "... the risks, if appropriately regulated, are minimal and acceptable given the potential benefits.", citing international developments on the management and regulation of xenotransplantation by the World Health Organisation and the European Medicines Agency.
Porcine endogenous retroviruses Endogenous retroviruses are remnants of ancient viral infections, found in the genomes of most, if not all, mammalian species. Integrated into the chromosomal DNA, they are vertically transferred through inheritance. Most breeds of swine harbor approximately 50 PERV genomes in their DNA. Although it is likely that most of these are defective, some may be able to produce infectious viruses so every proviral genome must be sequenced to identify which ones pose a threat. In addition, through complementation and genetic recombination, two defective PERV genomes could give rise to an infectious virus. There are three subgroups of infectious PERVs (PERV-A, PERV-B and PERV-C). Experiments have shown that PERV-A and PERV-B can infect human cells in culture. To date no experimental xenotransplantations have demonstrated PERV transmission, yet this does not mean PERV infections in humans are impossible. and eliminated infection from the pig to human cells in culture.
Ethics Xenografts have been a controversial procedure since they were first attempted. Many, including animal rights groups, strongly oppose killing animals to harvest their organs for human use. In the 1960s, many organs came from the chimpanzees, and were transferred into people that were deathly ill, and in turn, did not live much longer afterwards. Modern scientific supporters of xenotransplantation argue that the potential benefits to society outweigh the risks, making pursuing xenotransplantation the moral choice. None of the major religions object to the use of genetically modified pig organs for life-saving transplantation. Religions such as
Buddhism and
Jainism, however, have long espoused non-violence towards all living creatures.
History of xenotransplantation in ethics At the beginning of the 20th century when studies in xenotransplantation were just beginning, few questioned the morality of it, turning to animals as a "natural" alternative to
allografts. While
satirical plays mocked xenografters such as
Serge Voronoff, and some images showing emotionally distraught primates – whom Voronoff had deprived of their testicles – appeared, no serious attempts were yet made to question the science based on animal rights concerns. Despite this, it is considerably unlikely that animal suffering will provide sufficient impetus for regulators to prevent xenotransplantation. The patient should understand the risks and benefits of such a transplantation. A
public health dimension can also be considered. The Ethics Committee of the
International Xenotransplantation Association pointed out in 2003 that one major ethical issue is the societal response to such a procedure. The application of the four
bioethics principles is standardized in the moral conduct of laboratories. The four principles emphasize informed consent, the
Hippocratic Oath to do no harm, using skills to help others, and protecting the right to quality care. Though xenotransplantation may have future medical benefits, it also has the serious risk of introducing and spreading the infectious diseases, into the human population. Guidelines have been drafted by governments with the purpose of forming the foundation of infectious disease surveillance. ==See also==