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 genetically manipulated...

[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 will be.

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.


Cynomolgus monkeys (macaca fascicularis)
Credit: Mike Tourist





















































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