Touching Lives - September 2004
The match makers: bone marrow transplants
Imagine if the very treatment that was designed to make you well gave you a disease as severe as the illness it treated? Bone marrow transplantation transforms the lives of hundreds of desperately ill people each year. But unfortunately it will also trigger a debilitating and potentially fatal reaction called ‘graft-versus-host disease’ (GvHD) in up to 60 per cent of patients.
A recent Action Medical Research-funded project, led by immunologist Professor Mary Ritter at the Hammersmith Hospital in London, has built on work done through a previous Action Medical Research grant to make a crucial discovery about what might cause this devastating disease.
Bone marrow transplantation
Bone marrow is the spongy material in the middle of our bones which manufactures blood cells. As well as the red, disc-like blood cells which transport oxygen around the body, bone marrow produces white blood cells whose purpose is to fight off infection.
This manufacturing system is, however, disrupted in people affected by diseases such as leukaemia, anaemia, immune deficiency, or lymphoma. Either the wrong number of cells are produced, or cells are made that don’t do their job properly. As a result, patients are susceptible to diseases any other person would easily be able to fight off — and even minor infections can prove fatal.
However, ^just as malfunctioning organs can be replaced with organs provided by donors, bone marrow can also be transplanted^. The patient’s own malfunctioning bone marrow is killed by chemotherapy and new bone marrow is injected, giving the patient — in a successful transplant — a new, fully functioning immune system.
The first bone marrow transplant, in a patient suffering from leukaemia, was performed in 1969, and hundreds of such operations are now performed each year. However, there are often problems with making a bone marrow transplant work.
What can go wrong
There are up to 2,000 patients waiting for a bone marrow transplant at any given time. Of these, around one third have a brother or sister who can donate bone marrow. This gives the best possible chance of a good match. However, the majority of patients receive a transplant from an unrelated donor — and it is with unrelated donors that the risk of GvHD is at its highest. Professor Ritter explains,
“When a person is given an organ transplant, the body’s immune system sometimes recognises the organ as a foreign object and rejects it. With bone marrow transplants, it is the immune system itself that is being transplanted.
“So when something goes wrong, the effect is reversed: the immune system recognises the patient as different from itself, and starts attacking the body — usually the gut, liver or skin. And this reaction is most likely to happen with unrelated donors, where there are more likely to be more obvious differences between the donated cells and the patient’s body.
“The transplant itself may have been successful, in that the new immune system is attacking any cancer cells left in the patient’s body, but ^where GvHD occurs the immune system attacks normal cells as well^.”
The effects of GvHD range from diarrhoea to skin rashes and liver damage. Patients are given drugs to try to minimise the likelihood of GvHD, and while the symptoms are usually mild, it can become extremely severe, and all too often proves fatal.
The T-helper key
Professor Ritter’s work to combat GvHD has focused on a group of white blood cells called T-helper cells. T-helper cells have been called the ‘conductors of the immunological orchestra’. They are the key switches which keep the immune system running. Some destroy foreign bodies such as viruses, and some regulate or enhance immunological reactions.
In normal functioning, they look for foreign protein on the surface of the body’s own cells — an indication that a virus has infected the cell. The T-helper cell then destroys the infected cell. But in GvHD, the T-helper cells don’t discriminate properly between foreign bodies — the cancerous cells they should be destroying — and normal cells. In effect, the body starts to attack itself.
There are two main types of T-helper cells, called TH1 and TH2. TH1 cells usually kill malignant cells by causing inflammatory responses, while TH2 cells trigger an anti-inflammatory response.
“Originally,” says Professor Ritter, “we thought that TH1s were the baddies, the ones causing GvHD. TH1 and TH2 cells produce different types of water-soluble proteins called cytokines, which means it’s possible to measure how much of each type of cell is present in a sample by measuring the amount of each type of protein.
“So in our earlier Action Medical Research-funded project, we were looking at identifying which donors had lots of TH1. We thought transplants from these donors were more likely to trigger GvHD than others.”
However, the team’s latest grant has taken the research a step further, and in an unexpected direction.
The new findings
The most recent Action Medical Research grant was used to go ‘back to basics’. Previous tests had been very complicated, involving separating out dozens of samples of tiny numbers of cells and different types of protein.
This time, the team developed a very simple test. Just prior to a patient receiving a transplant, the team mixed some of their bone marrow cells in the laboratory with those of the donor. They measured the reaction the mix produced, and then over the following months monitored the patient’s clinical progress.
They observed a very strong association between the presence of one particular protein, called IL13, and the occurrence of graft-versus-host disease. This was a big surprise as IL13 indicated the presence of a TH2-type helper cell — rather than the TH1s that they thought were causing the problem!
This may sound like an added complication. However, as Professor Ritter explains, it is actually a very positive finding. Firstly, this new test is very easy to reproduce, and therefore easy for other researchers to use.
“^The particular strength of the test is that it mimics what happens in the body^, when the cells of the patient and the donor are all mixed together. By creating an environment which is as close as possible to that of the body itself, you can observe reactions which you might not have expected” — which is precisely what happened here.
Secondly, says Professor Ritter, the discovery of the IL13 association is itself very encouraging.
“This particular protein is produced in large amounts, so it’s much easier to detect in a sample. Plus, the association is very strong — the presence of this type of protein is a very robust indicator of whether the patient will be at risk of GvHD.”
The medical world is now closer to ensuring patients get the best possible match for their transplants. The simple test developed tells the clinician a great deal about the likely success or failure of a bone marrow transplant, and benefits for patients are in sight.
But there are questions to be asked about the function of the IL13 protein itself.
“We’re still not sure whether the IL13 is just an indicator of the presence of the TH2 cells, or whether it is actually doing something which affects the occurrence of GvHD,” says Professor Ritter.
“It’s a long way off, but in principle, ^if we found that IL13 was actually triggering GvHD, it might be possible to develop a drug which blocks it^. In fact, this kind of therapy is already used to treat rheumatoid arthritis. So it’s a real possibility.”
Part of a bigger picture
Professor Ritter has been working closely with clinician Dr Emma Morris, whose day-to-day experience as a consultant working with transplant patients brings home how crucial it is to find a way of preventing GvHD — “she’s our ‘reality check’”, says Professor Ritter.
“Up to 60 per cent of patients with an unrelated donor experience GvHD, and of those, 30-40 per cent will die from its effects,” explains Dr Morris. “What’s particularly tragic is that it is not the original disease — the lymphoma or leukaemia — which kills the patient, but the GvHD itself. And the only way of treating GvHD is to try to ‘switch off’ the immune system which is reacting against the body — in effect, taking the patient back to square one.”
“Of the transplant patients I saw on my rounds yesterday,” says Dr Morris, “three of them have been devastated by GvHD. ^They are no longer suffering from leukaemia, but the GvHD is so severe that they haven’t been able to go back to work^, and are being admitted to hospital up to eight times a year with GvHD related complications.”
Combating graft-versus-host disease would revolutionise bone marrow transplantation. Dr Morris describes this as “the Holy Grail of transplanting.” This Action Medical Research project has taken medical science a step further on the quest to reach that goal.