Avoiding Organ Rejection

17 February 2008

Interview with

Professor Megan Sykes, Harvard University

One of the biggest breakthroughs in the transplantation field has been the discovery of immuno-suppressants.  These are drugs that can partially switch off the immune system to prevent it from rejecting what the body sees as foreign tissue or non-self in a donor organ.  But this comes at a cost because the drugs are quite toxic and immuno-suppressed patients are also quite vulnerable to infections and cancers.

KidneysInstead scientists have been searching for ways to persuade the immune system to accept the new foreign tissue in a donor organ as its own.  Harvard's professor Megan Sykes and her colleagues have now managed to do that by giving patients a partial bone marrow transplant collected from the same donor as the kidney they're receiving.  Somehow the new bone marrow re-educates the immune system so that it ignores the new kidney and the patients no longer require any kind of immuno-suppression.

Megan - Since the very first time allogeneic transplants were performed, that means transplants that were done one individual to another, we've known that there is this rejection response that will destroy the graft unless something is done to prevent it.  So the success of allogeneic transplantation in patients in the last quarter century or so has depended on the use of immuno-suppressant drugs that suppress the immune system in a way that prevents the rejection of the graft.

Chris - There are some consequences of doing that though, aren't there?

Megan - Yes.  The trouble with that is these immuno-suppressive drugs suppress all immune responses so that the immune system is very generally compromised.  What that means is that the recipient is predisposed to developing infections and also cancers, diseases because it turns out the immune system is needed to protect us from developing cancers.  These are very serious side-effects and in addition there are a number of metabolic side-effects associated with these drugs and other unpleasant side-effects that people would like to avoid.

Chris - Why can't we re-programme the immune system to try to ignore what we're putting into the body and say 'this kidney I'm putting in is friend, not foe, don't attack it?'

Megan - Well, that's exactly what we have been attempting to do for quite a long time now and that we seem to have achieved in a small group of patients in a pilot study.  The approach that we have used involves use of bone marrow which contains cells that can form all of the blood-forming cells in the body.  It's been known for quite some years now that if bone marrow of two different individuals exists in one recipient that the donor bone marrow will educate the immune system in a way that allows the immune system to regard the donor as self and so the situation that you just described is created.  Any graft from that same donor is ignored because it looks like self.  The immune system has been educated to think that graft is self.

Chris - So what you're saying is that if you gave someone a kidney transplant, if you gave them a bone marrow transplant at the same time you can change what the immune system recognises as friend and foe.

Megan - That's right.  That's the idea.  Now what I've just described has been well-established in animal models for a while now and we have a pretty good understanding of how it works in the animal models.  The problem is, how do you go to an animal model from patients?  Patients who get organ transplants in general do quite well early on, especially in the first two years.  Another problem that I haven't mentioned yet with organs transplants that are performed is that despite all the chronic non-specific immuno-suppressive therapy there's a late phase of graft rejection called chronic rejection that really hasn't been improved by all this immuno-suppressive therapy so many grafts are lost in the 5, 10, 15 year period.  If we had this state where the immune system is re-educated as we've described, not only would we not need immuno-suppressive drugs but this more chronic type of rejection would also be prevented.

Chris - Could you talk us through, step-by-step, what you did in the pilot study with these patients?

Megan - Yes.  What it involves is giving the recipient some chemotherapy but at a dose that that is well below the dose that is used in a conventional bone marrow transplant and giving the drug that is the antibody that causes depletion of the rejecting lymphocytes, the T cells in the recipient and also affects the T cells in the donor bone marrow graft.

Chris - So you end up with a patient who, for a while at least has got 2 types of bone marrow.  They've got the donor who's going to give them, say the kidney, and they've got their own bone marrow as well.

Megan - Right, that's exactly right.

Chris - Then you put in the donor organ and at that time the immune system now is being told because the bone marrow is the same, don't reject this organ.

Megan - Right, so the kidney and the bone marrow are given at the same time and the bone marrow is present in the circulation for a period of just a few weeks.  Together the bone marrow derived cells in the kidney itself are doing some complex things that we're still trying to understand to re-educate the immune system and allow it to regard the kidney as self.

Chris - In the patients that you've tested this on so far what's been the outcome and are things still working for them now?

Megan - We've done five patients in this pilot study and four of them are currently doing very well.  They've been off immuno-suppression for a number of years.  One is approaching five years.  Their kidneys are being accepted despite the lack of any immuno-suppressant drugs.

Chris - So you've proved that this can work, at least on a small scale, with kidney transplants.  What about other organs, livers, hearts, lungs things like that.

Megan - The timing of the protocol is such that the organs and the bone marrow need to be transplanted at exactly the same time.  Yet the preparation of the recipient has to begin five or six days beforehand.  You need to know ahead of time that you're going to do the transplant.  At the moment this protocol limits us to live donors and the types of organs that are transplanted from living donors right now include kidneys, partial livers and sometimes lungs but hearts at the moment would not be relevant with this protocol.  However, the overall idea does work in animal models for any type of graft from the donor.  One of the things that we're working on in our animal models is modifying the regiment so that it will be possible to time it in a way that any organ can be transplanted.

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