Xenotransplantation
Program
A global shortage of
human organs for transplantation has lead to escalating waiting lists
for life saving transplants of hearts, kidneys, livers and other organs.
This has led the worldwide transplant community to review the options
for organ procurement. Increasing the donation rate from humans has been
calculated to have a relatively small impact on waiting lists while the
availability of successful bioartificial organs is clearly still some
way in the future.
The use of animals as
organ donors, or xenotransplantation, has been the subject of intense
research and debate over the past two decades. Ethical considerations
have led to the selection of the pig as the most likely source of organs
for humans, although significant biological barriers exist to achieving
long term organ survival and function in recipients. It is clear that
some genetic manipulation of the donor pigs will be required to overcome
these barriers.
The Scientific
Challenge
The survival of transplanted organs required the incorporation of
the organ into the human blood circulatory system. The major barriers to
solid organ xenotransplantation occur at the interface of the human
blood supply and the pig organ, where human blood flows through pig
blood vessels. As series of well defined reactions occur on the pig
endothelial lining cells of blood vessels. These are defined as
hyperacute, delayed and cellular rejection.
Hyperacute Rejection
(HAR) is the first biological obstacle confronting
xenotransplantation. HAR is the process by which unmodified,
vascularised xenografts undergo total failure within minutes. This
occurs because antibodies to cell surface molecules on pig tissues are
present in human serum, where they may play a role in defence against
pathogens bearing similar surface molecules. Following
xenotransplantation, these antibodies bind to the pig organ, triggering
the complement cascade and inducing endothelial cell activation. The
endothelium then rapidly loses its ability to regulate, which results in
oxygen deprivation and death of the organ or tissue.
If HAR is averted by
blocking complement activation, xenografts are still rejected within 2-7
days by an inflammatory process, collectively referred to as Delayed.
PPL has successfully 'knocked
out' the gene coding for alpha-1,3 galactosyl transferase (A1,3GT)
involved in HAR in pig
cells (press
release).
Xenograft Rejection
(DXR). During DXR, there is extensive xenoreactive antibody
deposition and cellular infiltration. The endothelial barrier function
is lost, allowing the migration of cells secreting inflammatory
cytokines into the graft.
A final hurdle to long
term xenograft survival is Chronic Rejection which is a T
lymphocyte mediated event. Following xenotransplantation, xenoreactive T
cells, activated either directly by the pig organ or indirectly by human
cells able to process and present the pig proteins, mediate the long
term destruction of the graft.
Regulatory Issues
Recent reports of endogenous porcine retroviruses have alerted the
xenotransplantation community to the need to evaluate safety issues
relating to the use of pigs as organ donors. PPL has been involved in
the discussion forum, attending meetings of both US and UK regulatory
authorities.
PPL's Programme in
Xenotransplantation
PPL, in collaboration with a leading transplantation immunology
group, amoungst others, is utilising it's core technologies of
transgenic livestock, nuclear transfer and animal husbandry, to devise a
comprehensive therapeutic package directed towards xenograft survival.
The PPL
Xenotransplantation Program addresses each of the immunological
reactions described above using a combination of nuclear transfer,
transgenic technologies and animal husbandry.
