New Treatment for Kidney Transplants -- In-Depth Doctor's Interview
David H. Sachs, M.D., an immunologist at Massachusetts General Hospital and a professor of surgery at Harvard School of Medicine in Boston, explains how a new discovery is making it easier for patients to tolerate a transplanted organ.
What does your recent discovery mean for transplant patients?
Dr. Sachs: The exciting thing about this new study is that it shows that we can fool the immune system, so to speak, into thinking that the transplant is self and therefore, the patient doesn't need to take immunosuppressive drugs to prevent rejection. There is no rejection because the transplant is considered by the immune system as part of the patient's own body.
How did this new method come about?
Dr. Sachs: The process is what we call immunologic tolerance and that means not reacting to -- not rejecting the tissue. The goal of being able to induce tolerance to transplants has been a goal of transplant immunologists for many years. It was shown first in animal models, first in mice and then in larger animals. And it's only recently that we have been able to take it to the clinic.
How did you come up with the idea to transplant bone marrow?
Dr. Sachs: It has been known for quite a few years that if the patient receives a bone marrow transplant for leukemia or lymphoma, and receives the bone marrow from a sibling, in general, it is very well matched. Then, if that same patient needs a kidney transplant years later and assuming the patient has remained on good enough terms with the sibling that gave the bone marrow originally, you don't need to use any immunosuppressive drugs. So we already know that bone marrow transplants, when successful, carry with them tolerance to any other tissue or organ from that same donor.
What do you mean by tolerance?
Dr. Sachs: Tolerance is the absence of rejection without exogenous immunosuppression -- that is without requiring drugs. So tolerance is acceptance of a tissue without the need for immunosuppressive drugs.
What is it about the bone marrow that allows that to happen?
Dr. Sachs: Well, all of us are continuingly making immune cells that can react against our own tissues. If something goes wrong, those cells will cause what we call autoimmunity or autoimmune disease. But in general any cell that reacts against self-antigens is eliminated in the thymus and it's eliminated by a process called negative selection. That process is based on the activity of cells from the bone marrow. So if there is bone marrow from both the recipient and the donor, then any new immune cell that forms that can react against either the donor or the recipient will be eliminated and what will be left is an immune system that is normal in every other respect, but it cannot react against the donor or the recipient.
By adding the bone marrow transplant, in essence what are you doing?
Dr. Sachs: First we have to eliminate the immune system that is already there and let it reform, but when the immune system reforms, it does so in the presence of both host and donor bone marrow cells and that is what teaches the immune system that both host and donor are self.
What precautions typically need to be taken to make sure a transplanted organ isn't rejected?
Dr. Sachs: In general, all the progress that has been made in the field of transplantation over the past several decades has relied on immunosuppressive drugs. Now these drugs are wonderful, they prevent the rejection of a transplant and allow people to resume a relatively normal life, but they all have side effects. They cause complications that are sometimes quite severe and in general if you have to take immunosuppression for the rest of your life then you have a much lower ability to fight infections and sometimes cancer.
As a doctor how do you feel knowing how successful it has been?
Dr. Sachs: Well, I think this procedure is not simple. It's a lot harder at the beginning than just taking an immunosuppressive drug to prevent rejection, but I think what you're doing is trading an initial harder procedure for a lifetime without having to take those immunosuppressive drugs.
From a personal point of view, how does it make you feel to know so many patients are doing so well?
Dr. Sachs: Well, it makes our whole team feel wonderful to see the success and to see these patients returning to a normal life. In particular some of these patients say this is the first time they've actually been normal since they had their disease.
How does it change a patient's life when they're not on immunosuppressive drugs?
Dr. Sachs: The same immunosuppressive drugs that have kept people alive with the transplant also have caused problems. Everybody has a weaker immune system and therefore, is more susceptible to infection, to viral or to bacterial infections, as well as to cancer. But in addition, different patients have different side effects from these drugs and some of them have renal failure, some complain of warts, some of them will have problems with loss of bone. It depends on the drug and it depends on the patient, but none of these drugs are without side effects.
Explain to me what happens during a bone marrow transplant?
Dr. Sachs: The reason the procedure is more difficult up front is that we have to eliminate the existing immune system first in order to train the new immune system to consider the donor as self. During that period between eliminating the mature cells that were already there and new cells forming, the patient is quite susceptible to infections for a couple of weeks. We keep the patients in a very clean environment to be sure they don't get infections, and we haven't had any problem with infections, but that's probably the most difficult part of the procedure.
Do you do the kidney transplant before the bone marrow transplant?
Dr. Sachs: No, we do them at the same time.
Do you have two different teams of doctors?
Dr. Sachs: That's right.
What does the process involve?
Dr. Sachs: Well, first what we do is give an antibody that eliminates the cells of the immune system that otherwise would reject the donor cells. Then we give bone marrow at the same time as the kidney, from the same donor. There are still host stem cells in that recipient, since we haven't eliminated all of the cells, just the mature cells. So new cells form from the recipient that now react against both host and donor cells as though they were self.
So it's almost like a third party cell, is that right because you're mixing them?
Dr. Sachs: We are all tolerant of our own tissues. We don't react against our own self. Why is that? That's because as T cells form in the thymus that can react against self, they are eliminated, because they react with a cell from the bone marrow that eliminates any cell that reacts strongly to self. If we have bone marrow from both recipient and donor, then any new T cell that forms that reacts either to self or to donor will be eliminated. So we are left with all the cells that can react against other problem antigens like bacteria and viruses, but none that react against either the host or the donor.
What's next for this research?
Dr. Sachs: This is only a small study. It's really just the beginning, just four of the first five patients who have now become tolerant of their kidneys. We have to treat more patients to be sure this is reproducible and we would like to extend the procedure to other organs, not just to the kidney. Eventually, even if this works really well and works for other organs, it will solve some of the problems that we have in transplantation today with regard to the quality of life of the patients, but it won't do anything for the fact that we've run out of donor organs. We just don't have enough to save the lives of all the people whose lives could be saved with a transplant. So we are hoping that this kind of procedure may also some day be used for xenotransplantation; that is the transplantation of organs from an animal to a human, in particular from the pig.
How would that work?
Dr. Sachs: Well, we've been working on special pigs that are exactly the same size as humans and have genetics that are very similar to humans with regard to transplantation. So we are hoping that eventually we'll be able to use this procedure there too. Now you have to remember that if you're going to cross a species, the immune reaction is even greater. So the idea of tolerance, of eliminating the immune response, will even be more important than for human transplants because that way we won't have to give much greater amounts of immunosuppressive drugs. I think that is the long term future for this field, and its also something we're working on.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
David H. Sachs, MD
Massachusetts General Hospital &
Harvard University School of Medicine
Transplantation Biology Research Center
Interested study participants: (617) 726-3706
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