John Dunning:
Consultant Cardiothoracic Surgeon
Xenotransplantation is the transplantation of tissues or organs between
animals of different species. It is not a new idea and references may
be found to the concept in ancient literature. A good example would
be the Chimera or Gryphon. However such creatures had fearsome reputations
and did not seem to be ideal choices for an emblem designed to represent
a field of science and surgery that is intended to be beneficial to
the human race.
In the early years of this century Princeteau (1905), Jaboulay (1906),
Unger (1910) and Neuhof (1923) all attempted to treat end-stage renal
failure in humans by the transplantation of renal tissue or whole kidneys
from a range of animal donors including rabbit, pig, goat, lamb and
monkey.
Interest in these alternatives waned as the underlying nature of the
immune response became established. At the same time viable human tissue
became available for transplantation with the use of living-related
donors for kidney transplantation. The brain stem death criteria were
also established, permitting the use of beating heart cadaveric donors
(i.e. a person in whom recovery to a stage permitting independent existence
without the support of a ventilator for breathing or drugs to maintain
the heart rate and blood pressure will not occur).
Organ transplantation from human donors (allotransplantation) is an
effective and established form of therapy for a wide variety of conditions
which bring about irreversible organ failure in the kidneys, heart,
lungs, liver, intestine, cornea or bone of an individual. So successful
has allotransplantation become that the demand for donor organs now
outstrips the supply of potential donor organs. Alternatives are being
sought and they include investigation into a mechanical or synthetic
substitute. However the complexities of producing a mechanical substitute
for a relatively simple organ such as the heart (which is essentially
a pump) are enormous and, as yet, have no satisfactory end in sight.
The challenges of replacing more complex metabolic organs such as the
kidneys or liver are greater. In this context it is natural to turn
once more to the concept of xenotransplantation and explore its feasibility.
The immune response
Our environment contains many infectious agents that could
do us great harm if we did not have defense mechanisms to deal with
them. All animals share a similar defense against such damaging agents
- the immune system. The immune system comprises a collection of molecules
and cells distributed throughout the body. Many of the molecules are
soluble factors which are borne in blood and tissue fluid and reach
all parts of the body. The cells circulate in the blood and migrate
from the blood vessels into tissue in response to a damaging stimulus.
Although these mechanisms are primarily responsible for protection
against infective agents, they are also capable of recognising tissue
as belonging to self or non-self. It is this ability which is so obstructive
to the transplant surgeon. The system will recognise any transplanted
tissue as being of non-self (unless from an identical twin) and will
therefore mount a response in an attempt to destroy the tissue. If transplantation
is to be successful, this rejection must be prevented
Preventing organ rejection
- Cell medicated immunity: molecule on the surface of the cells of
the transplant (called antigens) activate white blood cells called
T-cells. The T-cells play a major role in destroying the graft. Cell
medicated immunity is reduced if the antigens on the transplant are
matched with those of the recipient.
- Antibodies in the blood also play a role in organ rejection. This
is particularly true for transplants which are connected directly
to the recipient's blood supply such as the kidney, liver, heart or
lung.
- A slower form of rejection is described as acute rejection and develops
over 7-21 days. Acute rejection involves both T-cells and antibodies.
- Finally chronic rejection is almost entirely cell medicated and
occurs more than three months after the transplant.
Allotransplantation is only possible at all because these immune responses
may be modified by immunosuppressive therapy. Cyclosporin A which is
now the mainstay of immunosuppressive regimes is derived from a fungus.
It has several unpleasant side-effects including progressive kidney
damage which may induce kidney failure over a period of time. Additionally
corticosteroids and azathioprine are used. Again both drugs have unwanted
side-effects such as bone marrow suppression and leukopaenia. A significant
problem with all these measures is that the individual is more susceptible
to infection when they are taking these drugs, and a fine balance must
be achieved to prevent rejection without inducing overwhelming infection.
Xenotransplantation
The immune response in transplantation between animals of different
species is rather different from that seen in allotransplantation. When
the two species involved are closely related, such as non human primate
and man this is called concordant combination. If a transplant was performed
from a monkey to a human and no immunosuppressive drugs were used, the
tissue would be rejected over a period of days. This is similar to the
rejection seen with allotransplants. In contrast, the transplantation
of tissues between distantly related animals, for example, a pig and
a man is known as a discordant species combination. In this case rejection
would occur within a matter of minutes to hours and would be more violent.
At first, the rejection reaction directed towards the xenograft involves,
not the cells of the immune system, but the soluble factors in the blood.
A particularly important element of this part of the immune system is
the complement cascade (see Glossary, File 6). After a transplant, the
complement cascade is activated and it results in a hyperacute rejection
(HAR) in which the transplant is destroyed. The complement cascade may
also be very important in the development of post hyperacute rejection
mechanisms.
So, in order to prevent rejection of animal organs, it is necessary
to control the complement cascade. Molecules on the cell surface, called
complement regulators, are very important for controlling complement.
But these are species specific, so if a pig organ is transplanted into
a human, the complement regulators on the pig cells cannot control the
human complement cascade. Because the gene's coding for the human complement
regulators have now been isolated it has proved possible to transfer
this information into a line of pigs, creating transgenic animals. The
result is a normal looking pig with human complement regulators on the
surface of its organs which can be transplanted into a human. Early
evidence from the laboratory suggests that hyperacute rejection may
be avoided with this strategy. It is, however, clear that for successful
clinical xenotransplantation it will not be enough to control just one
element of the xenograft rejection response. Current immunosuppressive
protocols and drugs are not successful in controlling the rejection
of xenografts. So new strategies must be developed, at the same time
minimising possible adverse drug side effects.
Xenotransplantation of pig organs and tissue
There are a number of persuasive arguments which may be bought
to bare in the consideration of xenotransplantation:
- The ready availability of donor organs would allow all potential
recipients to benefit from treatment.
- With increased availability of organs the current indications for
transplantation could be re-evaluated and extended, so that patients
currently excluded from consideration for transplantation may also
benefit from this treatment.
- Transplant operations could be planned to fit in with routine work.
(Currently they are performed as emergency operations, and usually
take place through the night.)
- Problems associated with storage and injury to donor organs associated
with their ischaemic period (the time that the organ has no blood
supply from explantation from the donor to implantation in the recipient)
may be minimised.
- There exists the potential for pre-transplant manipulations of both
the donor and the recipient to permit modulation of the immune response,
with an accompanying improvement in long-term organ function and patient
survival.
Obstacles/Problems
Such arguments are indeed persuasive, but there are also a number of
obstacles to be overcome before xenotransplantation could ever be widely
accepted.
Relatively few studies have addressed the issues of physiological compatibility
between organs of different species. While a relatively simple organ,
such as the heart, may have a similar cross species physiology, other
organs with more complex metabolic and synthetic function probably will
not.
Another issue of major concern is that of the transmission of disease
from donor to man. The effect of transfer to an immunosuppressed recipient
of tissue which contains potential pathogens is unknown at this stage.
The future
A great deal of money and research effort is directed into
the field of xeno-transplantation at present. Over the last ten years
there have been enormous advances in the understanding of the components
of the xenograft rejection response. It is clear that this is a complex
reaction and we are only beginning to understand its secrets. However
there have been very encouraging results suggesting that clinical application
of disease is a realistic possibility in the near future. There are
outstanding issues concerning the transfer from an animal donor, and
the acceptability of the concept to the population, but it is likely
that these issues will also be resolved in time.
Meanwhile other research continues in an attempt to develop artificial
substitutes for organ replacement. They too are some way distant.
Our healthcare system must also focus more intently on preventative
medicine so that organ failure secondary to external influences, such
as drugs and diet, is reduced. Although in time this may make transplantation
obsolete it will take several generations for this to be achieved. Until
one, or all, of these solutions are achieved, our best therapy for a
fortunate few patients with end-stage organ failure remains allotransplantation:
a therapy which is only possible through the generosity of people who,
while they are grieving over the death of a much-loved friend or relative,
are thoughtful enough to offer organs for donation, giving a gift of
life to others.
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