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Transplant made to measure

Study shows how genetic mutations help to select donors of bone marrow

HÉLIO DE ALMEIDADistributed Production: bone marrow makes blood cellsHÉLIO DE ALMEIDA

Foreseeing a swifter recovery, or even the success, of a transplant of bone marrow depends on many factors, such as the patient’s clinical and nutritional conditions and the stage of the blood or immunological disease that made the doctors to turn to this expensive and delicate clinical procedure. Apart from this, the search for the best possible genetic-immunological compatibility between the donor and the receiver of the medulla – a liquid tissue that occupies the cavity in the bones and is responsible for the production of all the components of the blood – is crucial for the success of the operation. With this intent, the laboratories carry out tests on the blood of the patient and of the possible donors, usually a brother or sister or close relative of the patient.

The process of selecting the person who is going to give the medulla usually stops there. If the examinations indicate a low risk of rejection, the tissue graft is given the green light and is carried out. But recent work by a team of researchers from the University of São Paulo in Ribeirão Preto and from the Hospital Saint Louis, in Paris, advocates the idea that it is possible to take a step forward in the search for an almost perfect transplant, if medicine adopts an extra procedure: looking, above all into the donor’s DNA, but also in the receiver of the medulla, small mutations in genes linked to the inflammatory response and to the defense mechanisms of the organism.

After analyzing the clinical repercussions of a group of 12 genetic alterations technically called SNPs, orsingle nucleotide polymorphisms, (nucleotides are the chemical units with which the genetic code is written), the team of scientists concluded that some of these mutations can be used as useful markers for refining even more the search for the ideal transplant and foreseeing with more precision the patients’ clinical progress. “When there is more than one donor of medulla with a type of blood that is compatible with the receiver, we will be able to use these polymorphisms to choose which of them is the most suitable for giving the tissues”, says Marco Antonio Zago, of the School of Medicine of USP in Ribeirão Preto, one of the coordinators of the binational team involved in the work.

Lower risks
Published in the December 1st issue of theBlood magazine, the study shows that the use of medulla from a donor who carries the most dangerous of the 12 mutations – which affects the levels of production of the myeloperoxidase (MPO) enzyme, which assists the defense system in the task of fighting bacteria – brings an extra risk for the receiver of the tissue. In this case, the use of medulla with this polymorphism doubles the probabilities of the transplanted patient being a target for infections caused by bacteria. “The greater propensity to this kind of problem in the postoperative stage increases the chances of dying in the early months after the transplant”, explains Zago.

According to data from the work, which analyzed the recovery of 107 French transplanted patients, victims of acute or chronic myeloid leukemia (forms of cancer of the blood), the risk of there being a bacterial infection in people who received medulla from individuals with alterations in the myeloperoxidase gene was 39.5%. The occurrence of this kind of complication fell to 20.3% amongst transplanted patients who had taken in tissues from donors without this polymorphism.

At a molecular level, the mutation consists of the exchange of a nucleotide in a stretch of the MPO gene, in the number 463 position: while the majority of people show the nitrogenous guanine base (G) at this place, those who are carriers of polymorphism have the nitrogenous adenine base (A). From the functional point of view, this SNP brings about a reduction in the production of myeloperoxidase. Responsible for fighting infections of bacterial origin, this enzyme is normally found in large quantities in the leukocytes, the white cells that defend the organism. In healthy persons, although it likewise lessens myeloperoxidase production, polymorphism does not cause any major clinical repercussions. In patients awaiting a transplant, frailer from the immunological point of view, receiving the medulla from a donor with such SNP makes them more vulnerable to the action of bacteria.

This occurs because, in the preparation for the transplant, the doctors submit the sick to chemotherapy, which destroys the patients’ bone marrow and leukocytes. Straight after the operation, the patients are totally dependent on the donor’s medulla for producing new cells to defend against infections. At the first moment, the production of white globules by the new medulla is still small. “At this stage, any small variation in the production of leukocytes, such as caused by this polymorphism, can be crucial for the transplanted patient”, Zago comments. “In the future, we may perhaps develop antibiotics that stimulate the MPO’s gene”, explains the main author of the study, Vanderson Rocha, a Brazilian doctor who works at the Hospital Saint Louis.

Protective effect
The mutation in the gene of the MPO was, without a doubt, one of the greatest repercussion for the transplanted patient. This does not mean that the other polymorphisms studied did not prove useful for foreseeing possible problems with the patient who receives medulla from third parties. On the contrary. At least another three SNPs provided important data. The researchers found that a certain polymorphism, present in the IL-1Ra gene of some donors, has a negative effect on the transplanted patient: the mutation increases the risk of occurring the most serious and acute form of disease of the graft against the host, a sort of rejection by the body that receives it of the donor’s medulla.

We also discovered that one other polymorphism is associated with the transplanted medulla catching more quickly”, Rocha comments. This is an SNP found in the FcgR IIIb gene of certain donors, the benefic action of which consists of increasing the speed of recovery of the neutrophils, a kind of white blood cell specialized in fighting bacterial infections by eating the aggressor agent up (phagocytosis). The scientists also saw that the transplanted patients with an alteration to their IL-10 gene had a greater probability of developing the chronic form of the disease of the graft against the host.