Regulatory T cells trigger immunity to transplant rejection

22 May 2011

Interview with

Professor Robert Lechler, King's College London

Kat -   Also this week, UK scientists have made big step forward in the field of organ transplantation.  King's College researcher Robert Lechler and his colleagues have found a way to purify a rare population of immune cells called T-regs, short for regulatory T-cells, which help to switch off immune responses against donor organs that could help to reduce the risk of rejection.

[Robert explained the work to Chris Smith.]

Robert -   Organ transplantation, I would say, was one of the major successes of the second half of the last century in the field of medicine because it is lifesaving very often and life transforming almost always.  The success rates have improved steadily to the point that now, when you have a kidney or a heart, or a liver, these organs are successfully accepted in around 90% of cases and give a real lift of the quality of life of the patient.  So, it's a terrific success story.  However, there are three problems.  The first is the side effects and complications of the drugs that we have to give to make it work and these are drugs called immunosuppressive drugs that cause blanket depression of the immune system so that the immune system doesn't attack the transplant.  But it doesn't only depress the immune response to the transplant.  It makes your immune system less competent at protecting you against infections and it increases your risk of cancer.  So that's the first problem.  The second problem is that transplants tend to fail over time.  So the average kidney transplants from a dead donor would normally last around 10 or maybe 12 years and then gradually, they fail, and then the patient - if it's a kidney - goes back onto the kidney machine and waits for another transplant...

KidneysChris -   And is the reason for that failure, Robert, that despite the immunosupression, a gradual and inexorable damage is being unleashed upon the donor tissue by the patient's immune system?

Robert -   It's a very good question and the answer is partly yes.  Actually, the causes of late transplant failure are quite complicated and involve several different body systems but the immune system is definitely one of the drivers - you're right.  Then third limitation is the supply and demand problem that the whole field of transplantation has been a victim of its own success and so we just can't keep up with the numbers of organs that are needed and this is made worse by the organ failure business because of course, kidney patients get back on dialysis and so dialysis programmes are filling up with patients who are waiting for their second or third transplant.

Chris -   So what's your solution?

Robert -   So we, and many others around the world, have been working on the possibility of making the patient's immune system "selectively blind" - that's one way to put it - to the transplant.  The other language used is to make the patients "tolerant" - their immune system - tolerant to the transplant while leaving the immune system intact to protect the patient against infections and cancer.  That would solve all three of the problems I described because you wouldn't need long term drugs, number one.  Number two, this would probably limit the chronic transplant failure I mentioned, and thirdly, because transplants would last longer, then it would help to address the supply and demand issue.

Chris -   And how can you do that?

Robert -   There are several approaches that are being explored.  The one that we have taken is to exploit a population of white blood cells that we all have in order to protect us from what are called autoimmune diseases when the immune system attacks "self".  Many chronic diseases are caused by autoimmune reactions: diabetes, for example; multiple sclerosis; rheumatoid arthritis.  These are autoimmune diseases.  Most of us don't get those diseases and the reason is because we have this specialised population of white blood cells, they're called regulatory cells.  They're rather like policemen that keep the immune system from attacking self.  So, the question we posed is, could we take those cells and, if you like, divert their attention to regulate their response against the foreign bits of a transplanted organ.

Chris -   These cells are present in the body at very low frequency, so how can you get enough of them and also get just the ones from a mixed population that you need just to protect the target organ and not bring down the immune system comprehensively?

Robert -   It's a very good question.  So the answer is that the approach we've taken is we've isolated this specialised population of white cells from normal individuals and expanded them in the test tube, and expanded them by stimulating them with foreign antigens - the foreign proteins of a transplanted organ.  The ones that respond to the transplant's foreign proteins - those ones selectively grow and then you can make these cells expand to very large numbers in the test tube in order then to infuse them back in adequate numbers in vivo.  And because you have only expanded the ones that react to the transplant foreign proteins then they're only going to depress the immune response to the transplant rather than to all the other environmental antigens.

Chris -   And when you put them back into the patient, in your case you're using animals as a model obviously;  what about the longevity of those cells?  Do they last long enough to give us sustained immunosupression selectively against the target organ or are you going to have to keep repeating this process throughout the lifetime of that patient's graft in order to keep their immune system in check?

Robert -   The experiments that we've just described were getting close to working in a patient because they were working with human cells and it was a model of human transplant rejection because these were little pieces of human skin that we were protecting with these human cells.  So this was the human immune system working in an in vivo context, albeit it was in a mouse.  Earlier experiments we've done with mouse cells in a mouse have examined the question that you've just asked and we've looked at that longevity and we can find these cells 80 days after we put them in.  So you can find these cells for quite a long time. But, actually, what I would emphasise is that this kind of approach is really designed to tip the balance of the immune system towards tolerance, towards regulation, rather than rejection; and if you can tip that balance and reprogramme the immune system then, actually, it will tend to sustain that tolerant state itself, even if the cells that you initially put in subsequently die.

Kat -   And as we'll be hearing later, regulatory T-cells may actually be a key to helping beat allergies too and could also work to help treat autoimmune diseases like rheumatoid arthritis.  Let's hope so.  That was Kings College London scientist Robert Lechler and he published that work this week in the journal Science Translational Medicine.

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