Thoracic transplantation and stem cell therapy

Abstract

Lung and heart tranplantations are accepted standard therapies for end stage diseases and will maintain their importancy in the future. Potentially, transplantation at a cellular level using various forms of stem cells becomes an additional therapeutic approach.

Thoracic transplantation, Allotransplant, Donor pool, Xenotransplantation, Stem cell therapy

Repair of ‘irreversibly’ damaged thoracic organs currently is performed by total replacement of the diseased heart or lungs with an allotransplant. Both, heart and lung transplantation are well established procedures, offering short term (1-year) survival rates of 85% in specialised institutions [1–3].

At present, heart and lung transplantation, although beeing a flagship of cardiothoracic performance, count for a minority of cardiothoracic procedures and in few institutions the number of procedures reaches economical importance. However, this situation could likely change once the three limiting factors, organ availability, chronic rejection and long term side effects of immunosuppression, can be overcome [1].

For cardiac transplantation, significant enlargement of the available donor pool can be achieved only by improvements in organisational aspects together with improvements of the public acceptance of organ donation. Both factors are highly politically determined and dependant and there is clear scepticism that major improvements might be achieved in that regard [3].

For lung transplantation, additional approaches exist in the use of marginal donors, non-heart beating lung donors and living related and unrelated lung donation. All three concepts, although being in the center of current experimental and clinical investigations, still are in their infancy and ultimately will most likely not allow to provide the necessary number of organs needed [2].

In this situation, Xenotransplantation of genetically modified animals represents a different concept to overcome these limitations, but is at present unfortunately far away from clinical reality.

Although new treatment strategies and medications seem to have diminished the need for solid organ transplantation at least for the heart, this need might well further increase in the future due to postponement of problems and an ever aging population. In addition, any breakthrough in immunosuppressive strategies, will further increase this need due to widening of indications [3].

In the future, transplantation of both, heart and lungs, should not remain a palliative procedure, limited by the effects of chronic rejection and long term toxicity of immunosuppressive medication, but rather become a curative approach once solutions to these problems are developed [1]. The most promising concept certainly is to establish specific allogeneic tolerance. Although complete tolerance will most likely not be achieved soon, it might, however, become possible to establish a near-tolerance status which only requires a minimal amount of surveillance immunosuppression following an induction protocol. Finetunning of the necessary immunosuppression to achieve these near-tolerance conditions might then be performed through molecular profiling from peripheral lymphocytes [3].

Under these conditions, heart as well as lung transplantation seem to maintain its important role for treatment of various forms of end stage diseases in the future, however, will as well remain limited by organ availability.

Currently, the most promising alternative to transplantation of the heart undoubtedly represents transplantation at a cellular level using various forms of stemcells [4]. Although science in this area is very much in its infancy, hugh expectations exist to significantly influence the course of advanced ischemic heart diseases. These expectations are driven by the findings of mitotic ability of human adult cardiomyocytes, together with early evidence for functional improvement in post MI hearts after use of stem cells [5]. Undoubtedly, this form of treatment in particular implies the possibility that treatment of ischemic heart diseases further drifts away from cardiac surgery [5]. It will, therefore, be important that the combined role of surgical revascularisation procedures together with stem cell transfer is specified in future work and becomes central for cardiosurgical research.

Key issues:

• 1. How to enlarge organ pools and organ availability: TX organisation in general.

• 2. Documentation of superiority of TX over medical treatment.

• 3. Maintain and expand surgical involvement in IS protocols

• 4. How to combine the potentials of stem cell therapy with surgical revascularisation.

Appendix

Conference discussion

Dr F. Beyersdorf (Freiburg, Germany): Walter (Walter Klepetko), that was a very good talk. Thank you very much. You showed this one slide where you ask what would be the best homing procedure for the cells, by injecting it intraoperatively into the myocardium or do it intracoronary. To my knowledge, it is not known right now from all the different application routes, IV or intracoronary or intramyocardial, from the endocardial side or intramyocardial during crossclamping or even in the cardioplegic solution. Do you have any other knowledge or information?

Dr Klepetko: When I went through the literature, I realized that there is controversial evidence available right now. But we have to keep in mind the field is so early, I mean, this is something that is growing since the last two years, and maybe two years from now it will look completely different. Right now I think the point is we really have to try to be involved in that field and to have the potential to participate in upcoming new concepts.

Dr A. Haverich (Hannover, Germany): I very much enjoyed your presentation. I want to temper the enthusiasm a little bit, although I fully concur with your conclusions that we must be aware of potential applications in the future. I attended a meeting last Saturday in Dusseldorf, and there were like 20 presentations on stem cell therapy for cardiomyocyte replacement, and out of those, there were nine presentations that used nine different cell sources in various animal experiments. In all animal experiments and in the human experiments, ventricular function improved significantly, and in none of the studies was there any proof that those cells did actually integrate into the myocardium and did differentiate into cardiomyocytes. The opposite was true: there was no proof that any cardiomyocyte was found in any of the animal experiments or the human experiments. So we have to be very careful in reading those results for future use.

And the other thing is that Gustav Steinhoff from Rostock was the first to introduce hematopoietic stem cells, CD133, in the human situation. It was published in Lancet, as you know, and in that experiment as well, ventricular function also improved dramatically. The question that remains for me is what Friedhelm just also mentioned. Will it be the cardiolgists for the stem cell-based therapies by injection or will it be the surgeons at the time of operation. This is I think the key question. Alternatively, tissue engineering concepts using the same cell source maybe getting into surgical implantation. I am not sure if you want to comment on that.

Dr Klepetko: I think there is nothing really to comment. We have to be open for whatever direction the train goes in the future, this is the most important thing, to be aware of that and to be as early as possibly in the right direction to get hold of the method within our specialty. I think that is the only clear message right now.

Dr E. Rendina (Rome, Italy): You run one of the busiest practices of lung transplantation in Europe and you seem to have overcome the problem of shortage of donors. What in your opinion is, however, in the short midterm the best alternative to cadaveric donation? I am speaking of the short midterm, hoping that xenotransplantation will be available for the next decade or so.

Dr Klepetko: Non-heartbeating donation might raise such ethical concerns that in the long run it might not turn out as a valid concept which gains such an acceptance that we can expect a huge increase in the number of organs. I think we have to focus on the optimal use of available organs, and especially of the marginal organs, because the number of donors out there is quite large and the reasons why organs are rejected are also very large.

I am very much impressed by the Leuven group of Dirk van Raemdonck, who is really heavily working on resuscitating lungs. His group works on the concept to resuscitate lungs which are injured, overflooded, or even have an infectious problem, by putting them on a perfusion machine. I think this concept, if it works out might have a hughe potential for increasing the number of donor organs.

But the other thing is that still we do not use available organs in a way that we should, and I think Axel (Axel Haverich) might also want to comment on that because they have also quite an experience going out for lungs which are reported to be marginal or bad and then at the end they were found completely suitable for transplantation. And the same might hold also true for hearts.

For such a highly limited field like thoracic transplantation, where the resource is so precious, I think we have to make all efforts to have the best use of resources, which means that we have to make sure that the judgment of whether an organ is suitable or not for transplantation is really done by a highly experienced group and not by a center with a very low volume, which might, for understandable reasons, not want to take a risk in that regard.