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Transplants - are mice leading the way?

July 02, 2004

A new protocol for bone marrow transplants, which does not require the destruction of the recipient's immune system before transfer of the new bone marrow, is described by a group of Oxford scientists in the 6th of July issue of the Proceedings of the National Academy of Sciences of the United States of America 1.

Furthermore, Luis Gra'§a, Alain Le Moine, Herman Waldmann and colleagues from the University of Oxford, UK also found that following bone marrow transplant it is possible to successfully transplant other organs from the same donor, including skin, the most difficult organ to be successfully transplanted, into this now hybrid/chimeric bone marrow recipient.

These are extremely important discoveries in a world where the number of human tissue transplants is on the increase and are many times a one-time opportunity due to organs shortage. In Europe for example, hundreds of thousands of tissue transplants are performed each year, while only in 1999 as many as 750 000 people in the United States of America received human tissue, twice as many as in 1990.

Gra'§a, Le Moine and Waldmann's team have been working with mice for a number of years to find alternative protocols for safer and more effective organ transplantations. Because the immune system has evolved to react against any foreign intruder while remaining non-responsive against its own body, organs from other individuals are seen as foreign and so potentially dangerous which leads to their rapid destruction by the immune system, the body's defence mechanism. This creates serious problems in clinical transplantation and until now only the use of strong immunosuppressive drugs permits relative transplantation success. This however is not ideal, not only because rejection frequently occurs but also because these drugs compromise the entire immune system making individuals much more susceptible to infection or cancer

Gra'§a, Le Moine and colleagues work on an alternative model of tolerance based on the use of antibodies against several proteins found in the cells involved in organ rejection. Although the idea of antibodies is not new, these have been mostly used to delete entire populations of cells involved in the graft rejection process. This has the disadvantage of creating " holes" in the immune system and, like the immunosuppressive therapies widely used in transplant, increase the recipient/host's disease susceptibility.

What is interesting about the Oxford's scientists work is that their antibodies do not seem to kill the host cells involved in organ rejection but instead apparently re-programme these cells rendering them tolerant to the foreign organ while leaving the remaining immune system intact and fully operational. It is this specificity of the treatment, the capacity of only making tolerant the cells specific for the foreign organ while keeping the remaining immune system undamaged, that makes Gra'§a, Le Moine and colleagues' work so exciting.   

However, it is still not clear what the mechanism is behind this organ-specific tolerance and this has created problems to the development of human therapies. In the work now published, Gra'§a, Le Moine and colleagues investigate claims that CD4+CD25+ TCR+ cells, a group of cells of the immune system called this way because they express in their cellular membrane the three proteins: CD4, CD25 and TCR, are capable of regulating specific parts of the immune system without affecting the remaining immune cells and might be the cells responsible for inducing the type of organ transplant tolerance observed after Gra'§a and Le Moine's antibody therapy.

Unfortunately, the results by the team of scientists do not support the hypothesis. Nevertheless, this is still a very important result as it undoubtedly challenges the wide spread assumption that these cells are main regulators of immune responses.

Furthermore, Gra'§a, Le Moine and colleagues also describe a new protocol for bone marrow transplantation and successfully achieve, without immune deletion, a skin graft transplant between totally different donors and recipients a result never achieved before.

In fact, the team of scientists show how a course of their non-depleting antibodies, which are specific for proteins found on the membrane of the cells involved in graft rejection, when given at the same time as a bone marrow transplant, leads to complete acceptance of this foreign bone marrow. This is extraordinarily important, as the normal protocol for bone marrow transplants requires at least partial destruction of the recipient immune system so the new bone marrow would not be rejected, which leaves the patient severely immuno-compromised.
Gra'§a, Le Moine and colleagues also show for the first time that skin from a fully foreign donor is also accepted if this organ is transplanted together with bone marrow cells from the same donor while receiving the team's set of tolerogenic antibodies, something which has never been accomplished before in the absence of immunosuppression

These results are extremely significant. Not only Gra'§a and Le Moine's team describe a new, much more effective and safer way to control the immune system in bone marrow transplants, but they also report a new protocol that increases the probabilities of successful organ transplant to such a extent, that even the most difficult organ to transplant, a skin graft, can be successful. In a world where more and more transplants are necessary as result of an increasing aging population this is a critical breakthrough.

Finally, Gra'§a, Moine and colleagues capacity of " re-programme" the immune system without affecting its whole capacity to fight infection might prove extremely important also in other diseases where pathology results from deregulation of the immune system as it seems to be the case in diabetes, rheumatoid arthritis or multiple sclerosis.

Observatório da CiÙncia e do Ensino Superior