Overview
Xenotransplantation involves the transplantation of nonhuman tissues or organs into human recipients. The concept was pioneered a century ago, when transplanting human organs was considered ethically controversial. Grafts were quickly rejected, however, because of unknown forces later identified as immune responses.
Interest in xenotransplantation reemerged during the 1960s, when large advances were made in immunology. Chimpanzee kidneys have been transplanted into patients with renal failure.
In 1984, a baboon heart was transplanted into a newborn infant, Baby Fae, who had hypoplastic left heart syndrome and lived 20 days after heart surgery.
A baboon liver was transplanted to a patient with hepatic failure.
Porcine islet cells of Langerhans have been injected into patients with type 1 diabetes mellitus.
Porcine skin has been grafted onto burn patients,
and pig neuronal cells have been transplanted into patients with Parkinson disease and Huntington disease.
During these advances, several obstacles to the success of xenotransplantation have been identified. These include, but are not limited to, the following:
Preventing hyperacute rejection
Preventing acute vascular rejection
Facilitating immune accommodation
Inducing immune tolerance
Preventing the transmission of viruses from xenografts into humans
Addressing the ethical issues surrounding animal sources for xenografts and the appropriate selection of recipients (given that xenotransplantation remains experimental)
The rationale of xenotransplantation
The motivation for using animal sources for organ or tissue transplantation is driven by supply and demand. According to the United Network for Organ Sharing (UNOS), 114,518 people in the United States (approximately 32% of them under age 50 years) were waiting for organ transplantation as of November 8, 2018.
In 2017, 34,770 patients received transplants.
In light of the lack of supply of human organs for transplantation, several alternatives have been investigated and debated. Implantable mechanical devices have been explored in the field of cardiac transplantation. Research has increased in the area of transplanting embryonic cells across species and growing kidneys and endocrine pancreas cells in situ.
Organs from pigs have been the focus of much of the research in xenotransplantation, in part because of the public acceptance of killing pigs and the physiologic similarities between pigs and human and nonhuman primates. Xenotransplantation of organs from chimpanzees and baboons has been avoided, however, because of ethical concerns and fear of transmission of deadly viruses (see Biologic Barriers to Xenotransplantation).
Xenografts have been proposed as appropriate for infants who are physically too small to accommodate organs retrieved from adult or pediatric donors. Additionally, organs from animal sources could be transplanted into patients currently excluded from the human organ transplantation list. Finally, most patients perceive xenotransplantation as an acceptable bridge to transplantation of human organs in life-threatening situations.
History of the procedure
Alexis Carrel is known as the founding father of experimental organ transplantation because of his pioneering work with vascular techniques. Carrel and Guthrie contributed substantially to the science of transplantation from 1904-1906. They performed autogenous vein grafts, performed leg replantation in dogs, and developed the famous patch-graft technique for widening narrowed vessels. They also performed heterotopic experimental transplantation. Parts of a small dog were transplanted into the neck of a larger dog. They developed the buttonhole technique for anastomosis of donor and recipient vessels in kidney transplantation to prevent thrombus formation.
In 1906, Jaboulay transplanted kidneys from goats, sheep, and monkeys into humans. These attempts at kidney xenografting were unsuccessful. In 1910, Unger transplanted a nonhuman kidney into a man dying of renal failure, which caused death a little more than a day later. In 1932, Neuhof transplanted a lamb kidney into a patient with mercury poisoning. The patient survived for only 9 days. In 1946, Demikhov transplanted a heterotopic heart and lung; the animal survived for 9 hours.
The clinical interest in xenotransplants waned following the series of disappointing results and the realization that transplant failure was attributable to powerful unknown forces, which would eventually be identified as the body’s immune system. Scientific interest did not revive until the 1950s, following successful allografting of kidneys from identical twins. Michon and Hamburger successfully performed a living related-donor kidney transplantation in Paris in 1952; in 1954, Merrill and Murray, using no immunosuppression, performed the first kidney transplantation between monozygotic twins.
The advent of dialysis therapy during the 1940s and 1950s and its widespread availability in 1970s eventually made a significant and lasting impact on kidney transplantation. Hemodialysis established a bridge to transplantation and significantly expanded the population of patients that could benefit from kidney transplantation. Patients with end-stage renal disease had 2 therapeutic options: (1) dialysis and/or therapy or (2) an allograft (cadaveric or living related donor).
At that time, an understanding of transplant immunobiology and immunosuppressive drugs had just started to develop. Knowledge of organ procurement and preservation was extremely limited, severely curtailing the widespread clinical use of allografting. During this time, Starzl and colleagues (and other groups) were experimenting with xenotransplantation using chimpanzees or baboons.
The momentum of xenotransplantation was derailed in the 1990s with discovery of the porcine retrovirus. Concerns about the risk of cross-species infections resulted in moratoriums on clinical trials on xenotransplantation.
Definition
Xenotransplantation refers to any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (1) live cells, tissues, or organs from a nonhuman animal source or (2) human body fluids, cells, tissues, or organs that have had ex vivo contact with live nonhuman animal cells, tissues, or organs. (US Food and Drug Administration [FDA], 1999; FDA, 2001).
Xenotransplantation products must be alive, and circulation and return of patients’ blood must occur through live nonhuman cells. For example, human skin cells grown outside the body on a layer of nonhuman cells and then used in humans for skin reconstruction can also be considered a xenotransplantation product. This latter category of procedures was included in the definition because scientists believe that the potential for transmission of an infectious disease with such a procedure may be similar to that of implanting live nonhuman animal cells, tissues, or organs directly into a human recipient.
Xenotransplantation products include those from transgenic or nontransgenic nonhuman animals and composite products that contain xenotransplantation products in combination with drugs or devices. These include, but are not limited to, the following:
Porcine fetal neuronal cells
Encapsulated porcine islet cells
Encapsulated bovine adrenal chromaffin cells
Baboon bone marrow
External liver-assist devices using porcine liver or porcine hepatocytes
Nonliving biological products or materials from nonhuman animals, such as porcine insulin and porcine heart valves, are not classified as xenotransplantation products for the purposes of this definition.
Xenotransplantation products are subject to regulation by the FDA under section 351 of the US Public Health Service Act [42 U.S.C. 262] and the Federal Food, Drug and Cosmetic Act [21 U.S.C. 321 et seq]. In accordance with the statutory provisions governing premarket development, xenotransplantation products are subject to FDA review and approval.
Depending on the relationship between donor and recipient species, the xenotransplant can be described as concordant or discordant. Concordant species are phylogenetically closely related species. These species combinations include mouse to rat, baboon to cynomolgus monkey, or, presumably, nonhuman primate to human. Discordant species, on the other hand, are not closely related (eg, pig to mouse, pig to human).
A concordant recipient takes several days to reject an organ, whereas a discordant recipient mounts a violent, hyperacute response that leads to xenograft loss within a few minutes to a few hours. This difference in time to rejection is related to the presence or absence of preformed natural antibodies in discordant species pairs (described in Immunologic Barriers to Xenotransplantation).