Memorandum by the Department of Health
on Xenotransplantation and infection
1. Xenotransplantation is the transplantation
of tissue and organs between different species, and in particular
the transplantation of animal tissue into humans. The formal definition
currently used in the UK is:
any procedure that involves the use of live
cells, tissues and organs from a non-human animal source, transplanted
or implanted into a human or used for ex-vivo perfusion.
Ex-vivo perfusion is a means of partially taking
over the function of a failing organ by passing the patient's
blood through substitute tissues or organs outside the body.
2. There is currently, and will continue
to be, a shortage of human organs and tissue for transplantation.
Xenotransplantation is a potential solution to this shortage.
More likely, however, is the potential benefit from cell transplant
therapies in the treatment of conditions such as Parkinson's Disease,
Huntingdon's Disease, stroke, epilepsy, spinal injury and diabetes.
3. Before xenotransplantation can become
an accepted treatment, three major obstacles have to be overcome:
the risk of transmission of disease
from the donor animal to humans has to be minimal;
rejection of the "foreign"
tissue has to be prevented; and
there has to be evidence that the
animal organ or cells would function effectively in humans.
4. Recent scientific developments, including
genetic modification of source animals, may mean that the problem
of rejection of tissue transplanted between species can be overcome.
This increases the possibility of using animals to increase the
supply of organs and tissue to meet medical demand. However, it
also raises complex ethical and other issues, including safetyboth
of the individual and of the wider public, the efficacy of such
procedures and considerations of animal welfare.
5. The Government is advised on these issues
by the United Kingdom Xenotransplantation Interim Regulatory Authority
(UKXIRA), established in 1997 following the Government's acceptance
of the recommendations made in Animal Tissue into Human,
the report of the Advisory Group on the Ethics of Xenotransplantation
(the Kennedy report). The UKXIRA's role is to:
provide a focal point for xenotransplantation
activity in the UK;
provide a means of regulating xenotransplantation
and, in particular, to provide a process through which applications
to undertake xenotransplantation in humans can be considered;
consider the underlying evidence
about xenotransplantation developments and to consider whether
clinical trials can be justified.
6. All xenotransplantation procedures raise
similar safety issues, and uncertainty about the safety of xenotransplantation
continues to be a significant obstacle to its therapeutic use.
The potential for infectious agents to be passed from a source
animal, via a transplant (organ or cell), to a human recipient
and from the patient to the wider population is still a major
concern. The breeding of source animals in appropriate bio-secure
facilities can eliminate many of the obvious agents of concern,
but the question of, as yet, unknown infectious agents remains,
as does the question of agents which cannot be bred out of source
animalsin particular the porcine endogenous retrovirus
7. Since the establishment of the UKXIRA
much new evidence regarding infectious risk has emerged. Various
study groups have in the last couple of years reported evidence
of cross-species transmission of PERV using small animal (mice,
guinea pigs) models. The significance of these findings remains
unclear. Whether the same risk of infectious agent transmission
applies to all forms of xenotransplantation remains a matter of
debate. It may seem logical to suppose that a permanent whole-organ
xenotransplant represents a greater potential for infectious agent
transmission than, for example, the temporary passage of fluid
through a barrier-protected membrane. However, a single cell,
or a single viral particle, may present an infection risk. Until
further evidence comes to light, the UKXIRA considers it prudent
to assume that all xenotransplantation procedures carry a risk
of some degree.
8. Campaigning groups opposed to xenotransplantation
have called for a moratorium on clinical trials, one reason being
because of infectious risk. Until clear evidence becomes available
on the infection risks posed by any particular xenotransplant
technique, the UKXIRA will assess the level of risk posed by each
procedure balanced against the potential benefits on a case by
case basis. Account will be taken not only of the infection risks
involved, but also of evidence of efficacy and the ethical and
animal welfare considerations involved.
9. There has been considerable international
debate about the precise definition of xenotransplantation and
in particular whether certain procedures (both pre-existing and
newly emerging) require the same ethical and medico-scientific
framework as other forms of xenotransplantation.
10. In 2001, the Secretary of State for
Health accepted the UKXIRA's recommendation that the definition
of xenotransplantation currently used in the UK (see paragraph
1) should be changedas soon as was practicableto
bring it into line with the revised, broader, definition adopted
in the USA in 2000 (and which the Council of Europe is expected
to recommend for adoption by Member States):
any procedure that involves the transplantation,
implantation, or infusion into a human recipient of either (a)
live cells, tissues or organs from a non-human animal source,
or (b) human body fluids, cells, tissues or organs that have had
ex vivo contact with live non-human cells, tissues or organs.
11. The US definition encompasses a wider
range of possible products and procedures. Examples would include
procedures that involve the culturing of cells for transplant
through contact with a feeder layer of viable animal cells derived
from cell lines. Treatments using this type of process are already
in use and include the culturing of replacement skin for the treatment
of serious burns victims and for other forms of plastic surgery.
12. The UKXIRA had to consider the extent
of the risk of infectious agent transmission from these processes.
In skin replacement therapies, well-established mouse cell lines
are usually used and they have been used for a variety of scientific
and medical purposes for more than twenty years. There was, however,
considered to be a theoretical risk of infectious disease transmission,
13. The Department of Health commissioned
Professor George Griffin (a Member of the UKXIRA) and Dr Gee Yen
Shin, both of St George's Hospital Medical School, to assess the
possible infection risks to patients associated with this skin
culturing procedure and to produce recommendations to minimise
them. Professor Griffin's and Dr Shin's final report is expected
shortly. The use of such mouse cells for cell culture has also
been reviewed by the Advisory Committee on Dangerous Pathogens,
which concluded that the risk of transmission of mouse infectious
agents was very small.
14. In 2001, the UKXIRA commissioned an
assessment of the feasibility of developing a national infection
surveillance scheme for xenotransplantation purposes for public
health for the UK. It was to be based on the draft guidance from
the UKXIRA Infection Surveillance Steering Group (see paragraph
16) and to allow for future international surveillance requirements.
Recommendations for a scheme to be contracted to the Public Health
Laboratory Service (PHLS) have been submitted to the UKXIRA and
are under consideration. Any arrangement being developed with
the PHLS would be taken forward with the new Health and Protection
Agency from 1 April 2003.
15. The UKXIRA has published a number of
reports and literature reviews which are available from its website
First Annual Report, May 1997August
Second Annual Report, September 1998August
Third Annual Report, September 1999November
Fourth Annual Report, December 2000December
Guidance on making proposals to conduct
xenotransplantation on human subjects (1998).
Report of the workshop on porcine
endogenous retroviruses, 6 August 1998 (1998).
Infection Risks in Xenotransplantation
The Physiology of Xenotransplantation
16. Two draft reports are also available
from the UKXIRA website:
Draft Report of the Biosecurity Steering
Group of the UKXIRA: guidance notes on the biosecurity considerations
in relation to xenotransplantation.
Draft Report of the Infection Surveillance
Steering Group of the UKXIRA: further guidance on infection surveillance
aspects of xenotransplantation.