Important factor in transplant rejection identified

Each year, about 500 people in our country undergo a kidney transplant. 15 to 20% of these patients experience rejection symptoms. KU Leuven researchers have now revealed the importance of a newly identified mechanism of rejection. These results could increase the chances of a successful transplantation in the future.

After a transplant, the patient receives medication to suppress the immune system. This is because the chances are high that the body will recognise the organ as foreign, and will want to reject it. This therapy is effective, but 15 to 20% of the patients still experience rejection of the transplanted kidney. Professor Maarten Naesens and his colleagues from the Nephrology and Renal Transplantation Research Group at KU Leuven were able to prove that a newly identified mechanism of rejection, the ‘missing self’ mechanism, plays a significant role in patients undergoing a kidney transplant.

“The standard treatment that suppresses the immunity is based on the idea that the immune system attacks cells that are foreign to the body, and that thus do not belong there”, explains Professor Naesens. “Unless we carry out a transplantation between identical twins, there is always a difference between the tissue types of the donor and the recipient. This foreign tissue of the donor organ leads to an immune reaction, which we call transplant rejection. For our research, we followed a different approach: the ‘missing self’ principle.” This mechanism does not look for foreign tissue, but for the absence of the “own” tissue type. In this process, so-called Natural Killer cells search for self-proteins in the new organ. When they do not find these, they take action, and transplant rejection sets in.

Natural Killer cells

Natural Killer cells play an important role in the immune system, for example in fighting cancer. They check every cell they find to determine whether it is one of the host’s own cells. They do so using MHC proteins. Every cell in our body has MHC proteins, and those proteins are different for each person. The MHC proteins thus determine the ’tissue type’. The Natural Killer cells have specific KIR receptors that enable them to recognise the MHC proteins as self. In that case, they leave the cells on which these are present, undisturbed. When for example a tumour develops, the MHC proteins on these tumour cells may be disrupted. The KIR receptors on the killer cells no longer recognise the protein, are consequently activated and will attack and kill the cancer cell. This is a natural defence mechanism against cancer, and also against viral infections for example. Especially in oncology, research is carried out on how this system can be boosted in order to improve cancer treatment.

Recent research has shown that a similar mechanism may be activated after an organ transplant. The MHC proteins differ from person to person. Therefore, a donor kidney often contains other MHC proteins than those present in the body of the patient. The Natural Killer cells will do their work, and search for the body’s own MHC proteins, but will not find them. Consequently, they will attack the donor cells and eliminate them, thus rejecting the donor organ.

DNA analysis provides the solution

To map this ‘missing self’ mechanism, the researchers used DNA analysis: “If we have a donor organ with MHC proteins that are not attacked by the Natural Killer cells of the patient, then there is a much smaller chance of transplant rejection after the operation”, clarifies Jasper Callemeyn, physician and PhD researcher in the research group of Professor Naesens.

At this moment, a DNA analysis of the MHC molecules (tissue typing) is already a standard part of the procedure for an organ transplant. “The current DNA analysis that links a patient with a donor organ, is partly based on the similarity in tissue type”, explains Professor Naesens. We have extended this analysis, and also included the DNA analysis of the KIR receptors on the Natural Killer cells of the recipients. This way, we can predict whether the ‘missing self’ mechanism will be activated after a transplantation, which allows us to better assess the risk of transplant rejection.”

924 kidney transplants

For this study, the researchers explored data from 924 patients that underwent a kidney transplant in the University Hospitals Leuven. After the transplant, the result of the transplant, and the DNA of the patient and the donor organ, were put against one another. That’s how the researchers found that the chances of transplant rejection are strongly linked to a match between the MHC proteins of the donor organ and the killer cells of the patient.

“As a DNA analysis is already being carried out before a transplant, both with the recipients as with the donors, it will be relatively easy to apply our findings from the lab in practice”, states Jasper Callemeyn.

In addition to finding the right donor organ for the right patient, follow-up research is also needed. It could reveal if the ‘missing self’ mechanism of the Natural Killer cells could be suppressed with medication, for the prevention and treatment of transplant rejection.

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