TRANSCRIPT OF EXTRACTS OF UKXIRA ANNUAL OPEN MEETING
Chairman, Lord Habgood:
Re: form distributed on behalf of Carlton TV Organ Farm documentary:
"This is part of the effort to try to widen the public discussion
of xeno which we feel is very important."
Purpose of meeting: "Looking back at the progress of xeno
and launch annual report"
Professor Herb Sewell (Professor of Immunology, Nottingham University):
In the light of that development [the hDAF pig in 1995] and some
statements also from the company and from others that it would be
likely from that point onwards to move to some form of clinical
trial maybe within a year, there was some alarm, debate, and some
authorities great joy to say that we are really seeing a new dawn.
The Government in its wisdom decided it needed to have a view of
the potential consequences of this development for the patient,
the public at large, and indeed also for the animals that were being
[At the time of the Kennedy Committee's deliberations:]
We recognised that beyond hyperacute rejection, which appeared
to have been dealt with that there may well be some major immunological
problems downstream. And in particular, based on some experimental
data and some conjecture, we were particularly worried about another
form of rejection called delayed xenograft rejection, which comes
in some days to weeks after hyperacute, and can be quite vigorous
in its own destructive nature.
If there was to be any move towards clinical trials, and there
could be some way of containing rejection, that would have to be
with immunosuppressive drugs - at that time that was the dominant
thought - but those drug regimens should be of a level that would
be seen as acceptable and sensible if one was to extrapolate to
the clinical situation. In animal models systems people can sometimes
use very extreme protocols, and that in itself is a matter that
needs ethical debate. But many of those protocols really bear no
resemblance to reality in moving to man...
And it was said that if most of these things [overcoming rejection,
physiological function, virus transfer - e.g. PERVs] could be defined
in various ways or at various levels of sensitivity then there needs
to be discussions, not just amongst the experts, but engaging the
public about the risk margins that one would see as tolerable to
consider moving to therapeutic xenotransplantation.
... And I've made this point that because of the statements made,
partly by the companies and by other professionals, the public clearly
had the view that it was pretty imminent that we would have transplantation,
particularly of solid organs, and the targets were pig hearts and
kidneys into humans. This perhaps illustrates again why we need
to have this constant dialogue between the professionals and the
public in terms of expectation levels.
So, where are we from 1995 to this point?... The major part of
the talk is where I feel xeno' is going to.
... the problem of rejection is still with us, I believe, in a
major way, and efficacy is yet to be demonstrated in what I would
consider to be a meaningful way...
The problem of rejection and the acronym is for delayed xenograft
rejection, unlike hyperacute this is the combination of antibody
and cellular effects, it is a very potent form of rejection, and
using pre-clinical models of pig-to-primate transplants I believe
- and I'm prepared to debate that - that the evidence accrued suggests
that this has not currently been overcome with a level of immunosuppression
that would be acceptable for routine use in humans...
The best survival data has come from consortia involving Imutran
- they've shown for instance that the pig-to-baboon model in a very
limited number of animals that we can get survival up to 39 days
but with some significant co-morbidity. In their kidney transplant
model they get longer survival - some of the animals up to 70 days
plus, but again the suppressive regimen which involve a cocktail
of at least three potent immunosuppressives plus splenectomy I would
suggest would not be acceptable for human management. There is ongoing
problems about animal welfare and that should always be kept as
part of the calculus when one is looking at the way forward....
Solid organs: I think my reservations have been many already and
also I think these are the developments that need to be borne in
mind.... The efficacy data is poor, the immunosuppression data is
poor in the pig- primate model, and there is a constant question
of the unknown quantification of infection risk...
In my view, unless we can do something in particular about the
immune rejection phenomenon as well as get an acceptance of what
we see as tolerable risk of infection, progress in this area I am
certainly not seeing in less than a ten year scale, if at all.
Mr John Dark (Consultant Cardiothoracic Surgeon, Director (Cardio-Pulm.
Transplants), Freeman Hospital, Newcastle)
If we look at the situation with xeno'... There are what I would
have to regard as the disappointing results of the pig-to-primate
transplants that have been performed by a number of different groups
around the world and my own opinion is that measures which only
control hyperacute rejection would now seem to have been taking
us up somewhat of a blind alley. I can remember David White himself
from Imutran pointing out that the best we are achieving with these
measures is equivalent to an ABO mismatched transplant in allografting,
and if by accident we perform an ABO mismatch transplant in the
clinical world the only way of saving the patient is to rapidly
perform a re-transplant within days if at all possible, and I think
that is quite a useful point to make.
Xenotransplantation is the future of transplantation, and always
Professor Robin Weiss
In the retrospective surveys of people who have been exposed for
one reason or another to living pig tissue - in looking in their
blood for evidence of infection from PERV, it's essentially drawn
a blank. So the large study by Paradis et al that's already been
referred to, when for instance people had their blood perfused through
pig spleens - they were ordinary abattoir pigs in St Petersburg
and no specifically bred or clean pigs they were just checked out
to look healthy. And there was no evidence that they had passed
their virus onto humans as an infection that transferred into the
human tissue, although in 23 of those 100 exposed patients there
was long-term survival of some pig cells, or at least their DNA,
including the virus DNA embedded in it for several months after
the exposure. The extraordinary thing to my mind about this retrospective
study conducted by Novartis is that they looked only for PERVs even
those these were just ordinary abattoir pigs and they didn't attempt
to look for any of those other viruses that were just listed on
the previous slide [e.g pig hepatitis, circovirus] and although
I've pointed this out several times I never received an answer why
they didn't and why they shouldn't, you know, start tomorrow and
do that, because the material's there.