2024-01-29 11:12:47
It is one of the great fears after a kidney transplant: acute rejection of the donor kidney. To prevent this, people with a donor kidney use medications that suppress the immune system. However, these medications have serious side effects. In the short term, gastrointestinal complaints, high blood pressure and problems with sugar regulation. And in the long term there is even a greatly increased risk of cancer, infections and more serious illness from infections. This is because the anti-rejection drugs, so-called immunosuppressants, inhibit the entire immune system.
In principle, cutting back is safe
“The immune system consists of many types of immune cells. Ideally, you would only stop the immune cells that attack the donor kidney, but that is not possible yet,” says Dr. Michiel Betjes, nephrologist and researcher at Erasmus MC. “What we can do is reduce the dose of immunosuppressants for those who have a low risk of acute rejection. This is already happening, especially among the elderly with such a low risk. The results of our laboratory research now also substantiate that this should in principle be possible safely.” The research was conducted over the past four years by Dr. Amy van der List, who obtained her PhD, under the supervision of Betjes.
Moving on costs money
So the so-called proof of concept is there. Betjes would ideally like to go ahead now and develop a test that allows you to precisely measure people with a donor kidney: when can they reduce which medication by how much? “This requires clinical studies with patients. But we haven’t found the money for this yet. Pharma is not keen, because this reduces medication use.”
Yet the current results are already important. The evidence supports nephrologists to reduce immunosuppressants for those who can. Fewer medications means fewer side effects. And that improves the quality of life and life expectancy of a large group of kidney patients. About two-thirds of people with kidney failure are over 60. And this is also the fastest growing group.
Culprits in rejection
But what exactly did Betjes discover and how? “We have discovered which immune cells are exactly the culprits in rejection – that was not yet known. And we then measured this just before and years after the kidney transplant, in both older and younger people. That provided surprising insights.”
The immune cells that Betjes identified as the culprits of acute rejection are donor-specific T helper cells and cell-killing T cells. “These are so-called risky T cells. Did you have a lot of this before your kidney transplant? Then you also have a high risk of acute rejection.” T helper cells trigger an immune response. Cell-killing T cells then destroy the donor tissue. The ability to multiply to enormous numbers is important for these immune cells: the strength of an immune response largely depends on it.
DSH: no more immune response
For everyone, the risk of acute rejection is highest immediately after transplantation. After that, the chance drops. To almost zero: then there is donor-specific hyporesponsiveness (DSH), often 3 to 5 years after transplantation. Betjes: “In this phase, acute rejection is rare: your immune system simply no longer responds as strongly to the donor kidney. On other foreign tissue, by the way. That’s why it’s called ‘donor-specific’.”
But it was not known how DSH is formed. Betjes suspected in advance that over time, “for some reason” T helper cells can no longer respond or multiply, which reduces the risk of acute rejection. “We also thought that age influences this process.” Older people have a lower risk of acute rejection than younger donor kidney recipients. And they reach DSH (much) earlier.
Surprising: fewer T helper cells
However, research in the lab showed that not the reactivity but the number of donor-specific T helper cells decreased enormously. In both younger and older kidney transplant patients. “The striking thing was: this happened just as quickly in the elderly. They just had far fewer T helper cells to begin with, before the transplant.” This explains both the lower risk immediately after the transplant and the faster achievement of DSH. Betjes: “Age itself therefore has no direct influence.”
Another surprising outcome was that the cell-killing T cells in the elderly were much less able to multiply. “With fewer T helper cells, the chance of a starting shot is much smaller. This result means that a response to such a signal would also be much weaker. This also reduces the chance of rejection.”
Permanent decline
And is that decline permanent? “Certainly,” says Betjes. And precisely this is why nephrologists should in principle be able to safely reduce medication in transplanted elderly people with a low risk of acute rejection. “Once T cells are gone, they stay gone.” Can you stop taking immunosuppressants completely? “No, unfortunately,” Betjes admits. “A few T helper cells always remain present, as the memory of your immune system. You have to keep suppressing that. But the health benefit of significantly reducing medication is already enormous.”
Also options for high risk
In addition to clinical follow-up studies, Betjes also sees opportunities in the research results to help people at high risk of rejection. He draws a parallel with the defense and treatment against cancer. In certain forms of cancer, the body no longer fights cancer cells because the T helper cells involved produce proteins that inhibit themselves. Treatments have been developed that stop the production of these proteins. T cells then turn on again and cancer cells are cleared away.
Betjes: “Our results show that the same T-cell process is involved in rejection. Only we don’t want to turn T helper cells on, we want to turn them off. That should be possible on paper. Then we are on the way to medicines that only stop the immune cells that respond to the donor kidney.” And that is what Betjes thinks is the charm of science. “You have to be persistent in research. And sometimes you suddenly find more answers than you had hoped.”
This is how T cells cause rejection (or not)
Donor-specific T helper cells recognize foreign tissue. After initial contact, the T helper cell releases a signal by placing stimulation proteins on its exterior. Then all kinds of attack processes start up. Then the T helper cell checks again: is destruction really necessary?
If so, the T helper cell gives the starting signal: the cell will multiply and release cytokines that tell cells elsewhere what to do. Cell-killing T cells then attack and destroy the foreign tissue.
If a starting shot is not desired, T-cell inhibitory proteins, among other things, appear on the outside of the T-helper cell and inhibitory substances are released. The reaction is then calmed down.
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