Xenotransplantation
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
Donor
selection
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.
Physiology
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?
Immunology
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.
Cellular
rejection
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.
Ethics
There
are many ethical and religious views that would oppose breeding fellow
creatures in order to sacrifice them for spare parts.
