Will Xenotransplantation Ever Be Feasible?

Abstract

In several recent conferences, the principal questions have been whether Xenotransplantation technology should be encouraged and, if so, how it should be regulated. Because the prospect of successful transplantation of animal organs into humans is still remote, the rush to achieve consensus about clinical application 1,2 would be inexplicable were it not for two ostensibly unrelated issues. The first is the small but undeniable theoretical hazard of causing new human infections with the intermingling of tissues from different species. The second, advanced by animal-rights advocates, concerns the spiritual and ethical relationship of humans to animals. CLOSELY RELATED SPECIESThe rhetoric of these discussions has been heightened by the fact that all clinical organ xenotransplantations attempted since 1963 have failed, including >25 involving subhuman primate donors (19 reported or unreported chimpanzees, 10 baboons, and 1 [or 2] Rhesus monkeys). This experience began with Reemtsma and associates, 3 who proved in 1963 that kidneys from at least two subhuman primate donor species (Rhesus and chimpanzee) would not be rejected hyperacutely by humans. In fact, one of his chimpanzee xenografts functioned for 9 months. However, Reemtsma was the first to recognize that the humanoid qualities and threatened extinction of the chimpanzee would prevent its widespread use as a donor.Later in 1963, a team at the University of Colorado/Minnesota showed that baboon kidneys also would escape hyperacute rejection. In contrast to the chimpanzee, baboons flourished, and still do, in southern and central Africa. The six baboon renal xenografts of 1963 supported dialysis-free life for 6-60 days before undergoing fierce cellular rejection. 4 In addition, all of the baboon kidneys had occlusive endotheliolitis that was severe enough to cause regional parenchymal infarcts and islands of gangrene. We concluded by early 1964 that this humoral component of xenograft rejection could not be controlled with cell-directed immune suppression (azathioprine and prednisone at the time). A moratorium was selfimposed on further attempts. This hiatus lasted for 28 years, until investigations by Murase and colleagues 5 with the hamsterto-rat model appeared to justify a further trial. In this strain combination, in which the immune barrier resembles that between the baboon and human, 6 the combination of T-cell-specific immune suppression with tacrolimus plus B-cell-directed cyclophosphamide permitted the unprecedented routine survival of heart and liver xenografts for >100 days.In June 1992 and January 1993, two baboon-to-human orthotopic liver transplantations were performed in patients with chronic end-stage organ failure caused by hepatitis B virus infection.

Rejection of pig liver xenografts in patients with liver failure: Implications for xenotransplantation

“…[29][30][31] Identification of a clinical situation in which a xenograft is likely to have patient benefit is a limiting aspect of the clinical application of xenotransplantation. 32,33 Bridging xenograft trials would be performed in patients with either acute or decompensated liver failure. It is imperative to understand the impact that liver failure will have on liver xenograft rejection so that initial clinical attempts are not doomed to failure from oversights regarding the impact of patient disease.…”

Humans as second orangutans: sense or nonsense?

“…(2) There is a risk of pig‐to‐human disease transmission via an organ transplant [7, 8, 15]. On balance, the pig appears to be the donor animal of choice [8, 16–26].…”

Non‐human to human organ transplantation:Its biologic basis and a potential role for radiation therapy

“…(2) There is a risk of pig-to-human disease transmission via an organ transplant [7,8,15]. On balance, the pig appears to be the donor animal of choice [8,[16][17][18][19][20][21][22][23][24][25][26].…”