Xenotransplantation

Last updated
Xenotransplantation
Long axis echocardiography. Representative long axis view echocardiography, four weeks after myocardial infarction (MI), right before CMPC/placebo infusion. Thinning and akinesia of the septal apical wall due to MI can be appreciated.
MeSH D014183

Xenotransplantation (xenos- from the Greek meaning "foreign" or strange [1] [2] ), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. [3] Such cells, tissues or organs are called xenografts or xenotransplants. It is contrasted with allotransplantation (from other individual of same species), syngeneic transplantation or isotransplantation (grafts transplanted between two genetically identical individuals of the same species) and autotransplantation (from one part of the body to another in the same person).[ citation needed ] Xenotransplantation is an artificial method of creating an animal-human chimera, that is, a human with a subset of animal cells. In contrast, an individual where each cell contains genetic material from a human and an animal is called a human–animal hybrid. [4]

Contents

Patient derived xenografts are created by xenotransplantation of human tumor cells into immunocompromised mice, and is a research technique frequently used in pre-clinical oncology research. [5]

Human xenotransplantation offers a potential treatment for end-stage organ failure, a significant health problem in parts of the industrialized world. It also raises many novel medical, legal and ethical issues. [6] A continuing concern is that many animals, such as pigs, have a shorter lifespan than humans, meaning that their tissues age at a quicker rate. (Pigs have a maximum life span of about 27 years. [7] ) Disease transmission (xenozoonosis) and permanent alteration to the genetic code of animals are also causes for concern. Similarly to objections to animal testing, animal rights activists have also objected to xenotransplantation on ethical grounds. [8] A few temporarily successful cases of xenotransplantation are published. [9]

Bioprosthetic artificial heart valves are generally pig or bovine-derived, but the cells are killed by glutaraldehyde treatment before insertion, [10] therefore technically not fulfilling the WHO definition of xenotransplantation of being live cells. [3]

History

The first serious attempts at xenotransplantation (then called heterotransplantation) appeared in the scientific literature in 1905, when slices of rabbit kidney were transplanted into a child with chronic kidney disease. [11] In the first two decades of the 20th century, several subsequent efforts to use organs from lambs, pigs, and primates were published. [11]

Scientific interest in xenotransplantation declined when the immunological basis of the organ rejection process was described. The next waves of studies on the topic came with the discovery of immunosuppressive drugs. Even more studies followed Joseph Murray's first successful renal transplantation in 1954 and scientists, facing the ethical questions of organ donation for the first time, accelerated their effort in looking for alternatives to human organs. [11]

Non-human kidney to a human

In 1963, doctors at Tulane University attempted chimpanzee-to-human renal transplantations in six people who were near death; after this and several subsequent unsuccessful attempts to use primates as organ donors and the development of a working cadaver organ procuring program, interest in xenotransplantation for kidney failure dissipated. [11] Out of 13 such transplants performed by Keith Reemtsma, one kidney recipient lived for nine months, returning to work as a schoolteacher. At autopsy, the chimpanzee kidneys appeared normal and showed no signs of acute or chronic rejection. [12]

Non-human heart to a human

An American infant girl known as "Baby Fae" with hypoplastic left heart syndrome was the first infant recipient of a xenotransplantation, when she received a baboon heart in 1984. The procedure was performed by Leonard Lee Bailey at Loma Linda University Medical Center in Loma Linda, California. Fae died 21 days later due to a humoral-based graft rejection thought to be caused mainly by an ABO blood type mismatch, considered unavoidable due to the rarity of type O baboons. The graft was meant to be temporary, but unfortunately a suitable allograft replacement could not be found in time. While the procedure itself did not advance the progress on xenotransplantation, it did shed a light on the insufficient amount of organs for infants. The story made such an impact that the crisis of infant organ shortage improved for that time. [13] [12]

Non-human heart, lungs, and kidneys to a human

The first transplant of a non-genetically modified [14] [15] pig's heart, lungs and kidneys into a human was performed in Sonapur, Assam, in India in mid-December 1996, and was announced in January 1997. [14] The recipient was Purno Saikia, a 32-year-old terminally-ill man; he died shortly after the operation of multiple infections. [14] [16] The Indian cardiothoracic surgeon Dhani Ram Baruah and two of his associates, Jonathan Ho Kei-shing (of the Hong Kong-based Prince of Wales Medical Institute) [17] and C.S. James, performed the surgeries. [14] Baruah claimed that Saikia had failed to respond to conventional surgery, and that the patient and his family had consented to the procedure. [18]

All three involved in the surgery were arrested on January 9, 1997, [14] for the alleged violation of the Transplantation of Human Organs and Tissues Act of 1994. [14] [19] Baruah was dismissed in medical circles as a "mad scientist" and the procedure was dubbed a "hoax". Baruah himself signed a statement saying he had done no transplant, but then alleged that the confession was forced from him. [18] [15] They were found guilty of unethical procedure and culpable homicide and imprisoned for 40 days. [20] Dhani Ram Baruah's surgical institute was also found to be without necessary registration. [21]

Critics said Dhani Bam Baruah's claims and medical procedures were neither taken seriously nor accepted by the scientific community because he never got his findings scientifically peer-reviewed. [22] Past complaints of ethics violations during surgeries in Hong Kong by Baruah and Ho had occurred in 1992, when they had implanted heart valves, developed by Baruah, made of animal tissue. A year later, six patients died. The Asian Medical News reported that "grave concerns" were expressed "over the procedure and ethics of the implementation". [15]

Genetically engineered non-human kidney to a human

In September 2021, surgeons led by Robert Montgomery performed the first genetically engineered pig kidney xenotransplant to a brain-dead human at NYU Langone Health with no sign of immediate rejection (partly because the pig thymus gland was transplanted as well). [23] The kidney was procured from a pig with only a single gene modification: the removal of alpha-gal. [24]

In July 2023, surgeons from the NYU Langone Transplant Institute completed a transplant of a genetically modified pig kidney (along with the pig's thymus gland underneath it) into a patient declared brain dead but maintained on a respirator. [25] The patient had previously consented to be an organ donor, but his tissues were not considered suitable for transplant. The kidney came from an animal with a knocked-out gene for the production of alpha gal sugars, which has been implicated in immune response to mammalian tissue. [26] In order to ensure that renal function was only supported by the pig kidney, the team removed both of the patient's kidneys. The team has reported that the kidney has maintained optimal functioning for over a month, as evidenced by routine testing of creatinine and weekly biopsies. The team plans to monitor the patient for another month, pending approval by ethics board and his family.[ citation needed ]

In March 2024, Richard Slayman, a patient whose transplanted human kidney had failed, received a genetically engineered pig kidney xenotransplant from surgeons at Massachusetts General Hospital. [27] [28] This kidney has 69 genomic edits (3 gene knockout, 7 human gene insertion and 59 copies of the porcine retrovirus knockout) made by eGenesis, Inc. [29] Mr. Slayman died a few months later of unrelated causes, with no apparent rejection of the kidney. [30] Meanwhile, in April 2024, Lisa Pisano became the second person to receive such a kidney transplant. [30] [31] Because of "unique challenges" related to a mechanical heart pump she received along with the kidney, her kidney had to be removed due to "insufficient blood flow" late in May. [32]

Genetically engineered non-human heart to a human

In January 2022, doctors led by cardiothoracic surgeon Bartley P. Griffith and Muhammad M. Mohiuddin [33] at the University of Maryland Medical Center and University of Maryland School of Medicine performed a heart transplant from a genetically modified pig to a terminally ill patient, David Bennett Sr., who was ineligible for a standard human heart transplant. The pig had undergone specific gene editing to remove enzymes responsible for producing sugar antigens that lead to hyperacute organ rejection in humans. The US medical regulator gave special dispensation to carry out the procedure under compassionate use criteria. [34] The recipient died two months after the transplantation. [35]

In June and July 2022, surgeons at NYU Langone Health performed two genetically modified pig heart transplants into recently deceased humans. [36] The hearts were from pigs that had the identical 10 genetic modifications used in the University of Maryland Medical Center heart xenotransplantation in January 2022. All three hearts came from Revivicor, Inc., a facility based in Blacksburg, Va., and a subsidiary of United Therapeutics. [37]

On 20 September 2023, surgeons at the University of Maryland Medical Center in Baltimore performed a heart transplant from a genetically modified pig to Lawrence Faucette, a patient with terminal heart disease who was ineligible for a traditional heart transplant. On 30 October 2023, Faucette died after showing signs of organ rejection. [38]

Potential uses

A worldwide shortage of organs for clinical implantation causes about 20–35% of patients who need replacement organs to die on the waiting list. [39] Certain procedures, some of which are being investigated in early clinical trials, aim to use cells or tissues from other species to treat life-threatening and debilitating illnesses such as cancer, diabetes, liver failure and Parkinson's disease. If vitrification can be perfected, it could allow for long-term storage of xenogenic cells, tissues and organs so that they would be more readily available for transplant.[ citation needed ]

Xenotransplants could save thousands of patients waiting for donated organs.[ citation needed ] The animal organ, probably from a pig or baboon could be genetically altered with human genes to trick a patient's immune system into accepting it as a part of its own body. [40] They have re-emerged because of the lack of organs available and the constant battle to keep immune systems from rejecting allotransplants. Xenotransplants are thus potentially a more effective alternative. [41] [42] [43]

Xenotransplantation of human tumor cells into immunocompromised mice is a research technique frequently used in oncology research. [44] It is used to predict the sensitivity of the transplanted tumor to various cancer treatments; several companies offer this service, including the Jackson Laboratory. [45]

Human organs have been transplanted into animals as a powerful research technique for studying human biology without harming human patients. This technique has also been proposed as an alternative source of human organs for future transplantation into human patients. [46] For example, researchers from the Ganogen Research Institute transplanted human fetal kidneys into rats which demonstrated life supporting function and growth. [5]

Potential animal organ donors

Since they are the closest relatives to humans, non-human primates were first considered as a potential organ source for xenotransplantation to humans. Chimpanzees were originally considered the best option since their organs are of similar size, and they have good blood type compatibility with humans, which makes them potential candidates for xenotransfusions. However, since chimpanzees are listed as an endangered species, other potential donors were sought. Baboons are more readily available, but impractical as potential donors. Problems include their smaller body size, the infrequency of blood group O (the universal donor), their long gestation period, and their typically small number of offspring. In addition, a major problem with the use of nonhuman primates is the increased risk of disease transmission, since they are so closely related to humans. [47]

Pigs (Sus scrofa domesticus) are currently thought to be the best candidates for organ donation. The risk of cross-species disease transmission is decreased because of their increased phylogenetic distance from humans. [1] Pigs have relatively short gestation periods, large litters, and are easy to breed, making them readily available. [48] They are inexpensive and easy to maintain in pathogen-free facilities, and current gene editing tools are adapted to pigs to combat rejection and potential zoonoses. [48] Pig organs are anatomically comparable in size, and new infectious agents are less likely since they have been in close contact with humans through domestication for many generations. [49] Treatments sourced from pigs have proven to be successful such as porcine-derived insulin for patients with diabetes mellitus. [50] Increasingly, genetically engineered pigs are becoming the norm, which raises moral qualms, but also increases the success rate of the transplant. [51] Current experiments in xenotransplantation most often use pigs as the donor, and baboons as human models. In 2020 the U.S. Food and Drug Administration approved a genetic modification of pigs so they do not produce alpha-gal sugars. [52] Pig organs have been used for kidney and heart transplants into humans. [34] [23] [27] [31] [38]

Barriers and issues

Immunologic barriers

To date,[ citation needed ] no xenotransplantation trials have been entirely successful due to the many obstacles arising from the response of the recipient's immune system. Xenozoonoses are one of the biggest threats to rejections, as they are xenogeneic infections. The introduction of these microorganisms are a big issue that lead to the fatal infections and then rejection of the organs. [53] 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.[ citation needed ]

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). [1]

Hyperacute rejection

This rapid and violent type of rejection occurs within minutes to hours from the time of the transplant. It is mediated by the binding of XNAs (xenoreactive natural antibodies) to the donor endothelium, causing activation of the human complement system, which results in endothelial damage, inflammation, thrombosis and necrosis of the transplant. XNAs are first produced and begin circulating in the blood in neonates, after colonization of the bowel by bacteria with galactose moieties on their cell walls. Most of these antibodies are the IgM class, but also include IgG, and IgA. [49]

The epitope XNAs target is an α-linked galactose moiety, galactose-alpha-1,3-galactose (also called the α-Gal epitope), produced by the enzyme alpha-galactosyltransferase. [54] 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. [49]

The binding of XNAs initiate complement activation through the classical complement pathway. Complement activation causes a cascade of events leading to: destruction of endothelial cells, platelet degranulation, inflammation, coagulation, fibrin deposition, and hemorrhage. The result is thrombosis and necrosis of the xenograft. [49]

Hyperacute rejection is a severe, immediate immune response that occurs when a transplanted organ, such as a pig kidney, is rapidly attacked and destroyed by the recipient's immune system. In the context of pig kidney xenotransplantation, this type of rejection is triggered by pre-existing antibodies in the recipient's blood that recognize and bind to antigens on the surface of the pig kidney cells. These antigens, which are foreign to the human immune system, include certain carbohydrates and proteins that are not present in human tissues. The binding of these antibodies activates the complement system, leading to a cascade of events that cause widespread clotting and inflammation in the transplanted organ's blood vessels. As a result, the kidney quickly becomes ischemic (lacking adequate blood flow) and undergoes acute damage, often resulting in the organ's immediate loss.

Hyperacute rejection can severely affect the recipient’s body by leading to the rapid and complete failure of the transplanted kidney. This failure not only undermines the purpose of the transplant, which is to restore kidney function, but also poses serious health risks to the recipient. The sudden loss of kidney function can result in the accumulation of waste products and fluids in the body, causing symptoms such as swelling, electrolyte imbalances, and potential life-threatening complications. Furthermore, hyperacute rejection necessitates immediate medical intervention, often leading to the removal of the rejected kidney and the need to explore alternative treatment options, such as returning to dialysis or seeking another transplant source. Yang S, Zhang M, Wei H, Zhang B, Peng J, Shang P, Sun S.

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. [1]

Transgenic organs (Genetically engineered pigs)

  • 1,3 galactosyl transferase gene knockouts – These pigs do not contain the gene that codes for the enzyme responsible for expression of the immunogeneic gal-α-1,3Gal moiety (the α-Gal epitope). [55]
  • 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%. [56]
  • Expression of human complement regulators (CD55, CD46, and CD59) to inhibit the complement cascade. [57]
  • 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. [54]

Binding of the previously mentioned XNAs to the donor endothelium leads to the activation of host macrophages as well as the endothelium itself. The endothelium activation is considered type II since gene induction and protein synthesis are involved. The binding of XNAs ultimately leads to the development of a procoagulant state, the secretion of inflammatory cytokines and chemokines, as well as expression of leukocyte adhesion molecules such as E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). [49]

This response is further perpetuated as normally binding between regulatory proteins and their ligands aid in the control of coagulation and inflammatory responses. However, due to molecular incompatibilities between the molecules of the donor species and recipient (such as porcine major histocompatibility complex molecules and human natural killer cells), this may not occur. [54]

Overcoming acute vascular rejection

Due to its complexity, the use of immunosuppressive drugs along with a wide array of approaches are necessary to prevent acute vascular rejection, and include administering a synthetic thrombin inhibitor to modulate thrombogenesis, depletion of anti-galactose antibodies (XNAs) by techniques such as immunoadsorption, to prevent endothelial cell activation, and inhibiting activation of macrophages (stimulated by CD4+ T cells) and NK cells (stimulated by the release of Il-2). Thus, the role of MHC molecules and T cell responses in activation would have to be reassessed for each species combo. [54]

Accommodation

If hyperacute and acute vascular rejection are avoided accommodation is possible, which is the survival of the xenograft despite the presence of circulating XNAs. The graft is given a break from humoral rejection [58] when the complement cascade is interrupted, circulating antibodies are removed, or 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). [49]

Cellular rejection

Rejection of the xenograft in hyperacute and acute vascular rejection is due to the response of the humoral immune system, since the response is elicited by the XNAs. Cellular rejection is based on cellular immunity, and is mediated by natural killer cells that accumulate in and damage the xenograft and T-lymphocytes which are activated by MHC molecules through both direct and indirect xenorecognition.[ citation needed ]

In direct xenorecognition, antigen presenting cells from the xenograft present peptides to recipient CD4+ T cells via xenogeneic MHC class II molecules, resulting in the production of interleukin 2 (IL-2). Indirect xenorecognition involves the presentation of antigens from the xenograft by recipient antigen presenting cells to CD4+ T cells. Antigens of phagocytosed graft cells can also be presented by the host's class I MHC molecules to CD8+ T cells. [1] [59]

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. [1]

Overcoming cellular rejection

A proposed strategy to avoid cellular rejection is to induce donor non-responsiveness using hematopoietic chimerism. [40] 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. [1]

Chronic rejection

Chronic rejection is slow and progressive, and usually occurs in transplants that survive the initial rejection phases. [54] Scientists are still unclear how chronic rejection exactly works, research in this area is difficult since xenografts rarely survive past the initial acute rejection phases. Nonetheless, it is known that XNAs and the complement system are not primarily involved. [54] Fibrosis in the xenograft occurs as a result of immune reactions, cytokines (which stimulate fibroblasts), or healing (following cellular necrosis in acute rejection). Perhaps the major cause of chronic rejection is arteriosclerosis. Lymphocytes, which were previously activated by antigens in the vessel wall of the graft, activate macrophages to secrete smooth muscle growth factors. This results in a build up of smooth muscle cells on the vessel walls, causing the hardening and narrowing of vessels within the graft. Chronic rejection leads to pathologic changes of the organ, and is why transplants must be replaced after so many years. [59] It is also anticipated that chronic rejection will be more aggressive in xenotransplants as opposed to allotransplants. [60]

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. [61]

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. [61] An alternate clotting disorder, thrombosis, may be initiated by preexisting antibodies that affect the protein C anticoagulant system. Due to this effect, porcine donors must be extensively screened before transplantation. Studies have also shown that some porcine transplant cells are able to induce human tissue factor expression, thus stimulating platelet and monocyte aggregation around the xenotransplanted organ, causing severe clotting. [62] Additionally, spontaneous platelet accumulation may be caused by contact with pig von Willebrand factor. [62]

Just as the α1,3G epitope is a major problem in xenotransplantation, so too is dysregulated coagulation a cause of concern. Transgenic pigs that can control for variable coagulant activity based on the specific organ transplanted would make xenotransplantation a more readily available solution for the 70,000 patients per year who do not receive a human donation of the organ or tissue they need. [62]

Physiology

Extensive research is required to determine whether animal organs can replace the physiological functions of human organs. Many issues include:

Xenozoonosis

Xenozoonosis, also known as zoonosis or xenosis, is the transmission of infectious agents between species via xenograft. Animal to human infection is normally rare, but has occurred in the past. An example of such is the avian influenza, when an influenza A virus was passed from birds to humans. [63] 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. [64]

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. [64] Of particular concern are PERVS (porcine endogenous retroviruses), vertically transmitted microbes that embed in swine genomes. The risks with xenosis are twofold, as not only could the individual become infected, but a novel infection could initiate an epidemic in the human population. Because of this risk, the FDA has suggested any recipients of xenotransplants shall be closely monitored for the remainder of their life, and quarantined if they show signs of xenosis. [65]

Baboons and pigs carry myriad transmittable agents that are harmless in their natural host, but extremely toxic and deadly in humans. HIV is an example of a disease believed to have jumped from monkeys to humans. Researchers also do not know if an outbreak of infectious diseases could occur and if they could contain the outbreak even though they have measures for control. Another obstacle facing xenotransplants is that of the body's rejection of foreign objects by its immune system. These antigens (foreign objects) are often treated with powerful immunosuppressive drugs that could, in turn, make the patient vulnerable to other infections and actually aid the disease. This is the reason the organs would have to be altered to fit the patients' DNA (histocompatibility).[ citation needed ]

In 2005, the Australian National Health and Medical Research Council (NHMRC) declared an eighteen-year moratorium on all animal-to-human transplantation, concluding that the risks of transmission of animal viruses to patients and the wider community had not been resolved. [66] 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. [67]

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. [60] Due to the many deletions and mutations they accumulate over time, they usually are not infectious in the host species, however the virus may become infectious in another species. [49] PERVS were originally discovered as retrovirus particles released from cultured porcine kidney cells. [68] Most breeds of swine harbor approximately 50 PERV genomes in their DNA. [69] 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. [70] 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. [69] [71] To date no experimental xenotransplantations have demonstrated PERV transmission, yet this does not mean PERV infections in humans are impossible. [64] Pig cells have been engineered to inactivate all 62 PERVs in the genome using CRISPR Cas9 genome editing technology, [72] and eliminated infection from the pig to human cells in culture. [73] [74] [75]

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. [76] 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. [77] Modern scientific supporters of xenotransplantation argue that the potential benefits to society outweigh the risks, making pursuing xenotransplantation the moral choice. [78] None of the major religions object to the use of genetically modified pig organs for life-saving transplantation. [79] Religions such as Buddhism and Jainism, however, have long espoused non-violence towards all living creatures. [51] In general, the use of pig and cow tissue in humans has been met with little resistance, save some religious beliefs and a few philosophical objections. Experimentation without consent doctrines are now followed, which was not the case in the past, which may lead to new religious guidelines to further medical research on pronounced ecumenical guidelines. The "Common Rule" is the United States bio-ethics mandate as of 2011. [80]

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. [81] While satirical plays mocked xenografters such as Serge Voronoff, and some images showing emotionally distraught primates appeared – who Voronoff had deprived of their testicles – no serious attempts were yet made to question the science based on animal rights concerns. [81] Xenotransplantation was not taken seriously, at least in France, during the first half of the 20th century. [81]

With the Baby Fae incident of 1984 as the impetus, animal rights activists began to protest, gathering media attention and proving that some people felt that it was unethical and a violation of the animal's own rights to use its organs to preserve a sick human's life. [81] Treating animals as mere tools for the slaughter on demand by human will would lead to a world they would not prefer. [81] Supporters of the transplant pushed back, claiming that saving a human life justifies the sacrifice of an animal one. [81] Most animal rights activists found the use of primate organs more reprehensible than those of, for example, pigs. [81] As Peter Singer et al. have expressed, many primates exhibit greater social structure, communication skills, and affection than mentally deficient humans and human infants. [82] Despite this, it is considerably unlikely that animal suffering will provide sufficient impetus for regulators to prevent xenotransplantation. [51]

Autonomy and informed consent are important when considering the future uses of xenotransplantation. A patient undergoing xenotransplantation should be fully aware of the procedure and should have no outside force influencing their choice. [83] The patient should understand the risks and benefits of such a transplantation. A public health dimension can also be considered. [84]

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. [85]

The application of the four bioethics principles is standardized in the moral conduct of laboratories. [86] 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. [87]

Though xenotransplantation may have future medical benefits, it also has the serious risk of introducing and spreading the infectious diseases, into the human population. [88] Guidelines have been drafted by governments with the purpose of forming the foundation of infectious disease surveillance. [88] United Kingdom guidelines state that patients have to agree to "the periodic provision of bodily samples that would then be archived for epidemiological purposes", "post-mortem analysis in case of death, the storage of samples post-mortem, and the disclosure of this agreement to their family", "refrain from donating blood, tissue or organs", "the use of barrier contraception when engaging in sexual intercourse", "keep both name and current address on register and to notify the relevant health authorities when moving abroad" and "divulge confidential information, including one's status as a xenotransplantation recipient to researchers, all health care professionals from whom one seeks professional services, and close contacts such as current and future sexual partners." [88] The patient must abide by these rules throughout their lifetime or until the government determines that there is no need for public health safeguards. [88]

Xenotransplantation guidelines in the United States

The Food and Drug Administration (FDA) has also stated that if a transplantation takes place, the recipient must undergo monitoring for the rest of their lifetime and waive their right to withdraw. The reason for requiring lifelong monitoring is due to the risk of acute infections that may occur. The FDA suggests that a passive screening program should be implemented and should extend for the life of the recipient. [89]

See also

Related Research Articles

Histocompatibility, or tissue compatibility, is the property of having the same, or sufficiently similar, alleles of a set of genes called human leukocyte antigens (HLA), or major histocompatibility complex (MHC). Each individual expresses many unique HLA proteins on the surface of their cells, which signal to the immune system whether a cell is part of the self or an invading organism. T cells recognize foreign HLA molecules and trigger an immune response to destroy the foreign cells. Histocompatibility testing is most relevant for topics related to whole organ, tissue, or stem cell transplants, where the similarity or difference between the donor's HLA alleles and the recipient's triggers the immune system to reject the transplant. The wide variety of potential HLA alleles lead to unique combinations in individuals and make matching difficult.

<span class="mw-page-title-main">Organ transplantation</span> Medical procedure in which an organ is removed from one body and placed in the body of a recipient

Organ transplantation is a medical procedure in which an organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organs may be transported from a donor site to another location. Organs and/or tissues that are transplanted within the same person's body are called autografts. Transplants that are recently performed between two subjects of the same species are called allografts. Allografts can either be from a living or cadaveric source.

<span class="mw-page-title-main">Liver transplantation</span> Type of organ transplantation

Liver transplantation or hepatic transplantation is the replacement of a diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for end-stage liver disease and acute liver failure, although availability of donor organs is a major limitation. Liver transplantation is highly regulated, and only performed at designated transplant medical centers by highly trained transplant physicians. Favorable outcomes require careful screening for eligible recipients, as well as a well-calibrated live or deceased donor match.

<span class="mw-page-title-main">Transplant rejection</span> Rejection of transplanted tissue by the recipients immune system

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.

<span class="mw-page-title-main">Skin grafting</span> Surgical transplantation of skin

Skin grafting, a type of graft surgery, involves the transplantation of skin. The transplanted tissue is called a skin graft.

Allotransplant is the transplantation of cells, tissues, or organs to a recipient from a genetically non-identical donor of the same species. The transplant is called an allograft, allogeneic transplant, or homograft. Most human tissue and organ transplants are allografts.

<span class="mw-page-title-main">Kidney transplantation</span> Medical procedure

Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor or living-donor transplantation depending on the source of the donor organ. Living-donor kidney transplants are further characterized as genetically related (living-related) or non-related (living-unrelated) transplants, depending on whether a biological relationship exists between the donor and recipient. The first successful kidney transplant was performed in 1954 by a team including Joseph Murray, the recipient's surgeon, and Hartwell Harrison, surgeon for the donor. Murray was awarded a Nobel Prize in Physiology or Medicine in 1990 for this and other work. In 2018, an estimated 95,479 kidney transplants were performed worldwide, 36% of which came from living donors.

Transplantable organs and tissues may refer to both organs and tissues that are relatively often transplanted, as well as organs and tissues which are relatively seldom transplanted. In addition to this it may also refer to possible-transplants which are still in the experimental stage.

<span class="mw-page-title-main">Baby Fae</span> American infant and xenotransplant patient

Stephanie Fae Beauclair, better known as Baby Fae, was an American infant born in 1984 with hypoplastic left heart syndrome. She became the first infant subject of a xenotransplant procedure and first successful infant heart transplant, receiving the heart of a baboon. Though she died within a month of the procedure, she lived weeks longer than any previous recipient of a non-human heart.

Thymus transplantation is a form of organ transplantation where the thymus is moved from one body to another. It is used in certain immunodeficiencies, such as DiGeorge Syndrome.

<span class="mw-page-title-main">Heart transplantation</span> Surgical transplant procedure

A heart transplant, or a cardiac transplant, is a surgical transplant procedure performed on patients with end-stage heart failure or severe coronary artery disease when other medical or surgical treatments have failed. As of 2018, the most common procedure is to take a functioning heart, with or without both lungs, from a recently deceased organ donor and implant it into the patient. The patient's own heart is either removed and replaced with the donor heart or, much less commonly, the recipient's diseased heart is left in place to support the donor heart.

Robert Montgomery is the director of the Transplant Institute at NYU Langone Health.

Bernhard J. Hering is professor of surgery and medicine and executive director of the Schulze Diabetes Institute at the University of Minnesota, where he serves as Vice Chair of Translational Medicine in the Medical School's Department of Surgery and where he holds the McKnight Presidential Chair in Transplantation Science and the Jeffrey Dobbs and David Sutherland, MD, PhD Chair in Diabetes Research.

Xenotransfusion, a form of xenotransplantation, was initially defined as the transfer of blood from one species into the veins of another. In most cases, it is a transfer of blood between a non-human animal and a human. However, further experimentation has been done between various non-human animal species. This procedure can be performed without affecting the health of the donor, as only about 10% of their blood volume is used each time. Utilizing the unlimited blood supply from animal sources eliminates the risk of transmitting infectious diseases between humans.

<span class="mw-page-title-main">Paolo Brenner</span> German cardiac surgeon

Paolo Brenner is a German physician and a professor of cardiac surgery at the Department of Cardiac Surgery, Klinikum Großhadern of the Ludwig Maximilian University of Munich (LMU). He is known for his work in the fields of xenotransplantation, the advancement of artificial hearts, extracorporeal membrane oxygenation (ECMO) and lung transplantation.

Organ transplantation is a common theme in science fiction and horror fiction, appearing as early as 1925, in Russian short story Professor Dowell's Head. It may be used as a device to examine identity, power and loss of power, current medical systems; explore themes of bodily autonomy; or simply as a vehicle for body horror or other fantastical plots. Organ transplantation in fiction is often used as horror and something that harms the people involved, in contrast to how organ donation is presented in real life, as something hopefully good for those involved.

<span class="mw-page-title-main">Bruno Reichart</span> German cardiothoracic surgeon

Bruno Reichart is a retired German cardiothoracic surgeon who performed Germany's first successful heart transplant in 1981 and its first combined heart–lung transplant in 1983.

<span class="mw-page-title-main">Keith Reemtsma</span> American surgeon

Keith Reemtsma was an American transplant surgeon, best known for the cross-species kidney transplantation operation from chimpanzee to human in 1964. With only the early immunosuppressants and no long-term dialysis, the female recipient survived nine months, long enough to return to work.

A human chimera is a human with a subset of cells with a distinct genotype than other cells, that is, having genetic chimerism. In contrast, an individual where each cell contains genetic material from a human and an animal is called a human–animal hybrid, while an organism that contains a mixture of human and non-human cells would be a human-animal chimera.

Tissue transplantation is a surgical procedure involving the removal of tissue from a donor site or the creation of new tissue, followed by tissue transfer to the recipient site. The aim of tissue transplantation is to repair or replace tissues that are missing, damaged, or diseased, thereby improving patients' survival, functionality and quality of life.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Dooldeniya, M D; Warrens, AN (2003). "Xenotransplantation: where are we today?". Journal of the Royal Society of Medicine. 96 (3): 111–117. doi:10.1177/014107680309600303. PMC   539416 . PMID   12612110.
  2. ↑ Mitchell, C Ben (2000-05-10). "Xenotransplanation and Transgenics: The Need to Discuss Limits". Cbhd. Archived from the original on 2018-11-19. Retrieved 19 November 2018.
  3. 1 2 Xenotransplantation. Definition by the World Health Organization
  4. ↑ Sarah Taddeo, Jason S. Robert (2014-11-04). ""Hybrids and Chimeras: A Consultation on the Ethical and Social Implications of Creating Human/Animal Embryos in Research" (2007), by the HFEA". The Embryo Project at Arizona State University.
  5. 1 2 Tentler, J. J.; Tan, A. C.; Weekes, C. D.; Jimeno, A; Leong, S; Pitts, T. M.; Arcaroli, J. J.; Messersmith, W. A.; Eckhardt, S. G. (2012). "Patient-derived tumour xenografts as models for oncology drug development". Nature Reviews. Clinical Oncology. 9 (6): 338–50. doi:10.1038/nrclinonc.2012.61. PMC   3928688 . PMID   22508028.
  6. ↑ Kress, J. M. (1998). "Xenotransplantation: Ethics and economics". Food and Drug Law Journal. 53 (2): 353–384. PMID   10346691.
  7. ↑ Hoffman J, Valencak TG (2020). "A short life on the farm: aging and longevity in agricultural, large-bodied mammals". GeroScience . 42 (3): 909–922. doi:10.1007/s11357-020-00190-4. PMC   7286991 . PMID   32361879.
  8. ↑ "Interviews - Dan Lyons". PBS. Retrieved May 21, 2022.
  9. ↑ "Organ Transplants from Animals: Examining the Possibilities". Fda.gov. Internet Archive. Archived from the original on December 10, 2007. Retrieved May 21, 2022.
  10. ↑ Li KYC (2019). "Bioprosthetic Heart Valves: Upgrading a 50-Year Old Technology". Front Cardiovasc Med. 6: 47. doi: 10.3389/fcvm.2019.00047 . PMC   6470412 . PMID   31032263.
  11. 1 2 3 4 Reemtsma, K (1995). "Xenotransplantation: A Historical Perspective". ILAR Journal. 37 (1): 9–12. doi: 10.1093/ilar.37.1.9 . PMID   11528018.
  12. 1 2 Cooper, DK (January 2012). "A brief history of cross-species organ transplantation". Proceedings (Baylor University. Medical Center). 25 (1): 49–57. doi:10.1080/08998280.2012.11928783. PMC   3246856 . PMID   22275786.
  13. ↑ Bailey, L. L.; Nehlsen-Cannarella, S. L.; Concepcion, W.; Jolley, W. B. (1985). "Baboon-to-human cardiac xenotransplantation in a neonate". JAMA: The Journal of the American Medical Association. 254 (23): 3321–3329. doi:10.1001/jama.1985.03360230053022. PMID   2933538.
  14. 1 2 3 4 5 6 SCMP Reporter (15 Feb 1997). "The heart of darkness". South China Morning Post.
  15. 1 2 3 Banerjee, Ruben (January 15, 1997). "Pig heart transplant: Not many are buying the Assam doctor's story yet". India Today. Retrieved May 21, 2022.
  16. ↑ Maharashtra Herald, 11 Jan 11 1997, page 5
  17. ↑ Ruth Mathewson (16 Feb 1997). "Transplant surgeon to lose licence". South China Morning Post.
  18. 1 2 "Why the US Pig Heart Transplant Was Different From the 1997 Assam Doc's Surgery". The Wire Science. January 13, 2022. Retrieved May 21, 2022.
  19. ↑ M. Gnanapragasam (16–19 Jan 1997). "Perspectives in Medical Ethics". Bioethics in India: Proceedings of the International Bioethics Workshop in Madras: Biomanagement of Biogeoresources. University of Madras.
  20. ↑ Rahul Karmakar (January 13, 2022). "A pig heart transplant in Assam in 1997". The Hindu. Retrieved May 21, 2022.
  21. ↑ "The Infamous Cardiac Surgeon - Dr Dhani Ram Baruah, All You Need To Know". The Sentinel (Guwahati). October 23, 2021. Retrieved May 21, 2022.
  22. ↑ Agarwala, Tora (January 14, 2022). "After pig's heart transplant in the US, controversial Assam doctor points out had done historic surgery 24 years ago". The Indian Express. Retrieved May 21, 2022.
  23. 1 2 "Progress in Xenotransplantation Opens Door to New Supply of Critically Needed Organs". NYU Langone News. Retrieved May 21, 2022.
  24. ↑ Weintraub, Karen (October 19, 2021). "Pig Kidneys to the Rescue? Groundbreaking Transplant a Step Toward Solving our Organ Shortage". USA Today. Retrieved September 11, 2022.
  25. ↑ "Pig Kidney Xenotransplantation Performing Optimally After 32 Days in Human Body". NYU Langone News. Retrieved 2023-08-17.
  26. ↑ Krishna, N.; Krishna, S.; Krishna, R. (November 2017). "P112 Correlation between clinical findings and laboratory tests for alpha gal sensitivity". Annals of Allergy, Asthma & Immunology. 119 (5): S37. doi:10.1016/j.anai.2017.08.136. ISSN   1081-1206.
  27. 1 2 Rabin, Roni Caryn (21 March 2024). "Surgeons Transplant Pig Kidney Into a Patient, a Medical Milestone". New York Times. Retrieved 22 March 2024.
  28. ↑ Goodman, Brenda (21 March 2024). "Pig kidney transplanted into living person for first time". CNN. Retrieved 22 March 2024.
  29. ↑ Anand RP, Layer JV, Heja D, et al. (11 October 2023). "Design and testing of a humanized porcine donor for xenotransplantation". Nature. 622 (7982): 393–401. Bibcode:2023Natur.622..393A. doi:10.1038/s41586-023-06594-4. PMC   10567564 . PMID   37821590.
  30. 1 2 Emma Bowman (May 12, 2024). "The first person to receive a genetically modified pig kidney transplant has died". NPR . Retrieved 2024-05-13.
  31. 1 2 Rob Stein (April 24, 2024). "A woman with failing kidneys receives genetically modified pig organs". NPR. Retrieved 2024-05-13.
  32. ↑ Lauran Neergaard (May 31, 2024). "Woman is back on dialysis after doctors remove transplanted pig kidney". The Independent . Retrieved 2024-06-02.
  33. ↑ Kotz, Deborah (January 10, 2022). "University of Maryland School of Medicine Faculty Scientists and Clinicians Perform Historic First Successful Transplant of Porcine Heart into Adult Human with End-Stage Heart Disease". University of Maryland School of Medicine . Retrieved May 21, 2022.
  34. 1 2 "Man gets genetically-modified pig heart in world-first transplant". BBC News. January 11, 2022. Retrieved May 21, 2022.
  35. ↑ Neergaard, Lauran; Johnson, Carla K. (March 9, 2022). "US man who got 1st pig heart transplant dies after 2 months". Associated Press. Retrieved May 21, 2022.
  36. ↑ DeVries, Colin (July 12, 2022). "Successful Heart Xenotransplant Experiments at NYU Langone Set Protocol for Pig-to-Human Organ Transplants". NYU Langone Health . Retrieved September 11, 2022.
  37. ↑ Molteni, Megan (January 20, 2022). "After a Flurry of Firsts, Xenotransplantation is Suddenly Back in the Spotlight". Stat News . Retrieved September 11, 2022.
  38. 1 2 "Man who received the second pig heart transplant dies, hospital says". www.nbcnews.com. Associated Press. 2023-11-01. Retrieved 2023-11-01.
  39. ↑ Healy, D. G.; Lawler, Z.; McEvoy, O.; Parlon, B.; Baktiari, N.; Egan, J. J.; Hurley, J.; McCarthy, J. F.; Mahon, N.; Wood, A. E. (2005). "Heart transplant candidates: Factors influencing waiting list mortality". Irish Medical Journal. 98 (10): 235–237. PMID   16445141.
  40. 1 2 David H. Sachs (May 2018). "Transplantation Tolerance Through Mixed Chimerism: From Allo to Xeno". Xenotransplantation. 25 (3): e12420. doi:10.1111/xen.12420. PMC   6010074 . PMID   29913045.
  41. ↑ Platt JL, Cascalho M (2013). "New and old technologies for organ replacement". Current Opinion in Organ Transplantation. 18 (2): 179–85. doi:10.1097/MOT.0b013e32835f0887. PMC   4911019 . PMID   23449347.
  42. ↑ Van Der Windt, D. J.; Bottino, R; Kumar, G; Wijkstrom, M; Hara, H; Ezzelarab, M; Ekser, B; Phelps, C; Murase, N; Casu, A; Ayares, D; Lakkis, F. G.; Trucco, M; Cooper, D. K. (2012). "Clinical islet xenotransplantation: How close are we?". Diabetes. 61 (12): 3046–55. doi:10.2337/db12-0033. PMC   3501885 . PMID   23172951.
  43. ↑ Tisato V, Cozzi E (2012). "Xenotransplantation: An Overview of the Field". Xenotransplantation. Methods in Molecular Biology. Vol. 885. pp. 1–16. doi:10.1007/978-1-61779-845-0_1. ISBN   978-1-61779-844-3. PMID   22565986.
  44. ↑ Richmond, A.; Su, Y. (2008). "Mouse xenograft models vs GEM models for human cancer therapeutics". Disease Models and Mechanisms. 1 (2–3): 78–82. doi:10.1242/dmm.000976. PMC   2562196 . PMID   19048064.
  45. ↑ JAX® In Vivo Xenograft Services. JAX® NOTES Issue 508, Winter 2008
  46. ↑ Lewis, Tanya (2015-01-21). "Growing human kidneys in rats sparks ethical debate". CBS News. Retrieved 2015-09-26.
  47. ↑ Michler, R. (1996). "Xenotransplantation: Risks, Clinical Potential, and Future Prospects". Emerging Infectious Diseases. 2 (1): 64–70. doi:10.3201/eid0201.960111. PMC   2639801 . PMID   8903201.
  48. 1 2 Kemter, Elisabeth; Denner, Joachim; Wolf, Eckhard (2018). "Will Genetic Engineering Carry Xenotransplantation of Pig Islets to the Clinic?". Current Diabetes Reports. 18 (11): 103. doi:10.1007/s11892-018-1074-5. PMID   30229378. S2CID   52308812.
  49. 1 2 3 4 5 6 7 Taylor, L. (2007) Xenotransplantation. Emedicine.com
  50. ↑ Cooper, David; Ekser, Burcin; Ramsoondar, Jagdeece; Phelps, Carol; Ayares, David (2015). "The role of genetically engineered pigs in xenotransplantation research". The Journal of Pathology. 238 (2): 288–299. doi: 10.1002/path.4635 . PMC   4689670 . PMID   26365762.
  51. 1 2 3 REISS, MICHAEL J. (2000). "The Ethics of Xenotransplantation". Journal of Applied Philosophy. 17 (3): 253–262. doi:10.1111/1468-5930.00160. ISSN   0264-3758. JSTOR   24354019. PMID   11765766.
  52. ↑ Dolgin, Elie (2021-04-01). "First GM pigs for allergies. Could xenotransplants be next?". Nature Biotechnology. 39 (4): 397–400. doi:10.1038/s41587-021-00885-9. ISSN   1546-1696. PMID   33846652. S2CID   233223010.
  53. ↑ Boneva, RS; Folks, TM; Chapman, LE (January 2001). "Infectious disease issues in xenotransplantation". Clinical Microbiology Reviews. 14 (1): 1–14. doi:10.1128/CMR.14.1.1-14.2001. PMC   88959 . PMID   11148000.
  54. 1 2 3 4 5 6 7 8 Candinas, D.; Adams, D. H. (2000). "Xenotransplantation: Postponed by a millennium?". QJM. 93 (2): 63–66. doi: 10.1093/qjmed/93.2.63 . PMID   10700475.
  55. ↑ Latemple, D. C.; Galili, U. (1998). "Adult and neonatal anti-Gal response in knock-out mice for alpha1,3galactosyltransferase". Xenotransplantation. 5 (3): 191–196. doi:10.1111/j.1399-3089.1998.tb00027.x. PMID   9741457. S2CID   39194181.
  56. ↑ Sharma, A.; Okabe, J.; Birch, P.; McClellan, S. B.; Martin, M. J.; Platt, J. L.; Logan, J. S. (1996). "Reduction in the level of Gal(alpha1,3)Gal in transgenic mice and pigs by the expression of an alpha(1,2)fucosyltransferase". Proceedings of the National Academy of Sciences of the United States of America. 93 (14): 7190–7195. Bibcode:1996PNAS...93.7190S. doi: 10.1073/pnas.93.14.7190 . PMC   38958 . PMID   8692967.
  57. ↑ Huang, J.; Gou, D.; Zhen, C.; Jiang, D.; Mao, X.; Li, W.; Chen, S.; Cai, C. (2001). "Protection of xenogeneic cells from human complement-mediated lysis by the expression of human DAF, CD59 and MCP". FEMS Immunology and Medical Microbiology. 31 (3): 203–209. doi: 10.1111/j.1574-695X.2001.tb00521.x . PMID   11720816.
  58. ↑ Takahashi, T.; Saadi, S.; Platt, J. L. (1997). "Recent advances in the immunology of xenotransplantation". Immunologic Research. 16 (3): 273–297. doi:10.1007/BF02786395. PMID   9379077. S2CID   46479950.
  59. 1 2 Abbas, A., Lichtman, A. (2005) Cellular and Molecular Immunology, 5th ed., pp. 81, 330–333, 381, 386. Elsevier Saunders, Pennsylvania, ISBN   0-7216-0008-5, doi : 10.1002/bmb.2004.494032019997.
  60. 1 2 Vanderpool, H. Y. (1999). "Xenotransplantation: Progress and promise". BMJ. 319 (7220): 1311. doi:10.1136/bmj.319.7220.1311. PMC   1129087 . PMID   10559062.
  61. 1 2 Cowan PJ; Robson SC; d'Apice AJF (2011). "Controlling coagulation dysregulation in xenotransplantation". Current Opinion in Organ Transplantation. 16 (2): 214–21. doi:10.1097/MOT.0b013e3283446c65. PMC   3094512 . PMID   21415824.
  62. 1 2 3 Ekser B, Cooper DK (2010). "Overcoming the barriers to xenotransplantation: prospects for the future". Expert Review of Clinical Immunology. 6 (2): 219–30. doi:10.1586/eci.09.81. PMC   2857338 . PMID   20402385.
  63. ↑ Beigel, J.; Farrar, J.; Han, A.; Hayden, F.; Hyer, R.; De Jong, M.; Lochindarat, S.; Nguyen, T.; Nguyen, T.; Tran, T. H.; Nicoll, A.; Touch, S.; Yuen, K. Y.; Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5 (2005). "Avian Influenza A (H5N1) Infection in Humans". New England Journal of Medicine. 353 (13): 1374–1385. CiteSeerX   10.1.1.730.7890 . doi:10.1056/NEJMra052211. PMID   16192482.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  64. 1 2 3 Takeuchi, Y.; Weiss, R. A. (2000). "Xenotransplantation: Reappraising the risk of retroviral zoonosis". Current Opinion in Immunology. 12 (5): 504–507. doi:10.1016/S0952-7915(00)00128-X. PMID   11007351.
  65. ↑ FDA. (2006) Xenotransplantation Action Plan: FDA Approach to the Regulation of Xenotransplantation. Center for Biologics Evaluation and Research.
  66. ↑ "The Australian National Health and Medical Research Council's 2005 statement on xenotransplantation" (PDF). Archived from the original (PDF) on 2008-07-22. Retrieved 2008-11-06.
  67. ↑ Dean, Tim (December 10, 2009). "Xenotransplantation ban lifted in Australia". Life Scientist. Archived from the original on 2009-12-15. Retrieved May 21, 2022.
  68. ↑ Armstrong, J. A.; Porterfield, J. S.; De Madrid, A. T. (1971). "C-type virus particles in pig kidney cell lines". The Journal of General Virology. 10 (2): 195–198. doi: 10.1099/0022-1317-10-2-195 . PMID   4324256.
  69. 1 2 Patience, C.; Takeuchi, Y.; Weiss, R. A. (1997). "Infection of human cells by an endogenous retrovirus of pigs". Nature Medicine. 3 (3): 282–286. doi:10.1038/nm0397-282. PMID   9055854. S2CID   33977939.
  70. ↑ Rogel-Gaillard, C.; Bourgeaux, N.; Billault, A.; Vaiman, M.; Chardon, P. (1999). "Construction of a swine BAC library: Application to the characterization and mapping of porcine type C endoviral elements". Cytogenetics and Cell Genetics. 85 (3–4): 205–211. doi:10.1159/000015294. PMID   10449899. S2CID   1496935.
  71. ↑ Takeuchi, Y.; Patience, C.; Magre, S.; Weiss, R. A.; Banerjee, P. T.; Le Tissier, P.; Stoye, J. P. (1998). "Host range and interference studies of three classes of pig endogenous retrovirus". Journal of Virology. 72 (12): 9986–9991. doi:10.1128/JVI.72.12.9986-9991.1998. PMC   110514 . PMID   9811736.
  72. ↑ "Xenotransplantation: How Pig Organs Could Be Transplanted into Humans". Animal Biotech Industries. March 19, 2018. Archived from the original on 2018-11-06. Retrieved November 5, 2018.
  73. ↑ Zimmerman, Carl (Oct 15, 2015). "Editing of Pig DNA May Lead to More Organs for People". The New York Times.
  74. ↑ "eGenesis | Our Approach | Producing Human-compatible Organs". egenesisbio.com.
  75. ↑ Weisman, Robert (March 16, 2017). "Startup eGenesis pushes toward goal: transplanting pig organs into humans". The Boston Globe.
  76. ↑ PETA Media Center: Factsheet: Xenotransplantation Archived June 26, 2010, at the Wayback Machine . Peta.org. Retrieved on 2013-10-17.
  77. ↑ Sharp, Leslie (2013). The Transplant Imaginary Mechanical Hearts, Animal Parts, and Moral Thinking in Highly Experimental Science. University of California Press. p. 38. ISBN   9780520277960.
  78. ↑ Cooper, David K. C.; Groth, Carl G.; McKenzie, Ian F. C.; Goldman, Emanuel; Fano, Alix; Vanderpool, Harold Y. (2000). "Xenotransplantation". BMJ: British Medical Journal. 320 (7238): 868–869. doi:10.1136/bmj.320.7238.868. ISSN   0959-8138. JSTOR   25187509. PMC   1127208 . PMID   10731189.
  79. ↑ Rothblatt, Martine (2004). Your Life or Mine. Burlington, VT: Ashgate Publishing Company. pp. 109–110. ISBN   978-0754623915.
  80. ↑ von Derdidas, Ihrwir (2009) A More Modest Proposal Archived July 12, 2011, at the Wayback Machine . Hotel St. George Press.
  81. 1 2 3 4 5 6 7 Rémy, Catherine (2009). "The Animal Issue in Xenotransplantation: Controversies in France and the United States". History and Philosophy of the Life Sciences. 31 (3/4): 405–428. ISSN   0391-9714. JSTOR   23334492. PMID   20586139.
  82. ↑ Anderson, M. (2006). "Xenotransplantation: A Bioethical Evaluation". Journal of Medical Ethics. 32 (4): 205–208. doi:10.1136/jme.2005.012914. ISSN   0306-6800. PMC   2565783 . PMID   16574873.
  83. ↑ Ellison T. (2006). "Xenotransplantation—ethics and regulation". Xenotransplantation. 13 (6): 505–9. doi:10.1111/j.1399-3089.2006.00352_3.x. PMID   17059575. S2CID   9831264.
  84. ↑ Kaiser M. (2004). "Xenotransplantation—ethical considerations based on human and societal perspectives". Acta Veterinaria Scandinavica. Supplementum. 99: 65–73. PMID   15347151.
  85. ↑ Sykes M; D'Apice A; Sandrin M (2003). "Position Paper of the Ethics Committee of the International Xenotransplantation Association". Xenotransplantation. 10 (3): 194–203. doi:10.1034/j.1399-3089.2003.00067.x. PMID   12694539. S2CID   9145490.
  86. ↑ Sharp, Leslie (2013). The Transplant Imaginary Mechanical Hearts, Animal Parts, and Moral Thinking in Highly Experimental Science. University of California Press. p. 45. ISBN   9780520277960.
  87. ↑ Sharp, Leslie (2013). The Transplant Imaginary Mechanical Hearts, Animal Parts, and Moral Thinking in Highly Experimental Science. University of California Press. p. 18. ISBN   9780520277960.
  88. 1 2 3 4 Florencio, Patrik S.; Ramanathan, Erik D. (2001). "Are Xenotransplantation Safeguards Legally Viable?". Berkeley Technology Law Journal. 16: 945. JSTOR   24116896. PMID   15212014 . Retrieved May 21, 2022.
  89. ↑ United States Food and Drug Administration. Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of XTx Products in Humans. Washington, DC: US FDA, 2001
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.