Aspirations for xenotransplantation
The shortfall between the number of available organs for transplantation and the number of patients on the transplant waiting lists is ever widening. One solution to this that has been explored since Jaboulay’s first efforts in the 1900s is the use of animal organs, so-called xenotransplantation. In spite of much research, xenotransplantation has failed to achieve the successes hoped for, and with every new finding more hurdles appear to slow its progress.
Many xenotransplants have been performed, ranging from kidney, liver and heart transplants using dog, goat, pig or primate organs, to the transplantation of specialised cells in an attempt to cure diabetes or Parkinson’s disease. None has yet been successful.
Barriers to success
It is generally agreed that the favoured animal for mass breeding as donors for transplantation is the pig, for the following reasons.
· The animals are of a similar size to man, compared with primates such as baboons, which are much smaller.
· Organs are anatomically similar to those in man.
· Breeding programmes are well established, and gestation is short.
· Genetic manipulation has been shown to be possible.
In the paragraphs that follow we have assumed that the pig is the donor; similar considerations apply whatever the species chosen.
There are several physiological considerations to xenotransplantation.
1. Environmental differences. There are several differences in the environment in which organs exist in pig and man.
• Temperature: the core temperature of a pig is 2°C higher than man at 39°C.
• Blood pressure: the pig’s blood pressure is lower than that of a human. Will a pig heart be able to support an effective blood pressure in man? Similarly, what will be the effect of a normal human blood pressure on pig organs such as the kidney?
2. Protein differences. There are subtle differences in structure and efficacy of some pig proteins compared with man. For example some of the clotting factors (e.g. factor V) exist in far higher concentrations in pig than man, the significance of which is not clear. Among the vast number of metabolic processes and proteins that are produced by the liver it is unlikely that all will be compatible with man, which makes liver transplantation from pig to man the least likely xenotransplant to succeed.
3. Regulatory proteins exist on endothelium to prevent inappropriate activation of protective mechanisms such as complement and coagulation. Pig liver produces pig complement, but the proteins involved in regulating human complement do not have the same regulatory effect on pig complement. Similarly the regulatory proteins on pig endothelium that stop clot forming are not effective against primate coagulation factors, so thrombosis is a common experimental finding when transplanting pig hearts into primates.
4. Hormone differences. While some pig hormones are known to be efficacious in man, such as insulin, it is not clear whether human hormones will have the same effect on pig organs, and whether the same degree of regulation of hormone secretion will occur.
5. Longevity. Most animals have a shorter life span than man. Will organs from pigs be able to support life for as long as a human organ, or will they suffer changes of senescence more quickly?
Humoral response: natural antibodies
Man posses natural antibodies to a carbohydrate residue on pig cells known as Gal-α-1,3 Gal, which is produced by the enzyme α-galactosyl transferase. This is present in many mammals but not New World primates or man. These pre-formed natural antibodies (XNAbs) cause hyperacute rejection, a process that involves the XNAbs binding to the porcine cells and fixing complement. XNAbs arise as a consequence of an immune response to enteric bacteria that contain the same residues; the XNAbs are absent at birth but appear soon after.
Strategies to overcome XNAb-mediated hyperacute rejection Genetic manipulation of pigs has resulted in strains that bear human complement regulatory proteins on the cell surface (DAF, MCP and CD59). These proteins protect the cells from attack by human complement, even after the XNAbs have bound. More recently strains have been developed that do not express Gal-α-1,3 Gal (‘Gal knockout’ pigs). Neither strategy seems to abolish completely a humoral response against the xenograft.
The major histocompatibility complex of the pig is different to that of man, and as such it was thought this would favour transplanta- tion across species since xenorecognition of the pig proteins on pig MHC molecules would not be possible. It turns out that xenorecognition occurs via the indirect pathway, with pig proteins presented to human T cells on human antigen-presenting cells, and effector T cells are active against pig cells. Moreover, there is also a significant innate immune response against the xeno-antigens.
Zoonoses: endogenous retroviruses
A zoonosis is the transmission of an infectious agent from one species to another. One such example is believed to be the human immunodeficiency virus, a retrovirus that was originally found in primates in Africa. Research has shown that, as with other mammalian species, there are many different endogenous retroviruses in the pig genome (PERVs), the significance of which is unclear, but some have been shown to be capable of infecting human cells in culture. However, in the few cases where humans have had pig tissue implanted in the past, such as porcine skin to cover burns, there is no evidence of viral transmission to date.
There are many ethical and religious views that would oppose breeding fellow creatures in order to sacrifice them for spare parts.