And yet they are rejected
The relationship with the donor did not save the macaques from rejection of other people's stem cells
Polina Loseva, N+1
French scientists have discovered that stem cell transplantation, even from a genetically compatible donor, causes immune rejection in the body of crab-eating macaques (Macaca fascicularis).
Despite the fact that it develops more slowly than in the case of cells from an incompatible donor, this means that it will not be possible to use such therapy without suppressing the activity of immunity in humans yet. The study is published in the journal Nature Communications (Baden et al., MHC matching fails to prevent long-term rejection of iPSC-derived neurons in non-human primates).
Organ and tissue transplantation from a donor to a recipient is always associated with the risk of rejection. The solution could be the patient's own stem cells: tissues identical to the damaged ones can be grown from them. If there are not enough stem cells, you can take adult cells from any organ and reprogram them into induced pluripotent cells, and then grow the desired type of tissue from them. In this case, the patient should be insured against an immune response – although recent studies in mice have shown that new mutations arise during reprogramming, to which the immune system can respond with aggression.
However, the patient's own cells do not always save: for example, this does not work if a person suffers from a genetic disease. In this case, it is necessary to resort to donor stem cells. At the same time, it is still unclear to what extent the tissues that can be grown from them will be compatible with the recipient's body.
Romina Aron Baden and colleagues from the Francois Jacob Institute of Biology conducted an experiment with cell transplantation on crab-eating macaques. Quinolinic acid, a substance that provokes hyperactivity and death of nerve cells, was injected into the monkeys' brains. In this way, scientists imitated the processes that occur in the brains of patients with Huntington's disease. The animals were supposed to be treated with precursors of nerve cells that were grown from induced pluripotent stem cells.
Crab-eating macaques turned out to be a convenient object for research, since one of their populations, living on the island of Mauritius, is known for its genetic homogeneity. Over the time of settlement of the island, these monkeys did not interbreed with other populations, so it is not difficult to find a genetically compatible donor among them.
As a rule, compatibility is determined by MHC proteins (major histocompatibility complex, major histocompatibility complex). In the mammalian body there is a separate group of immune cells – natural killers, which are programmed to kill any cells if they do not detect the usual set of MHC proteins on them. Each person has six types of MNS, and the more of them coincide with the recipient's MNS, the better the transplant will take root.
In an experiment with macaques, scientists used three types of transplants. The first is autologous: own cells were reprogrammed into pluripotent cells, nerve cell precursors were grown from them and transplanted into the brain at the site of injury. The second one is genetically compatible: a donor with an identical set of MNS was selected for the recipient macaque. The third is incompatible: an animal with a dissimilar set of MNS became a donor. In none of the cases did the scientists use immunosuppression to allow the immune system to respond to the transplant.
The researchers assessed the state of the animals' brains three and six months after surgery. It turned out that in all three cases, the tissue took root in the brain, and the progenitor cells continued to divide and give rise to neurons. When transplanted from an incompatible donor, the tissue recovered the worst, and lacunae remained at the site of damage. If the donor and recipient were compatible, then the recovery was successful.
Lacunae at the site of brain damage three months after surgery. From left to right: incompatible donor, autologous transplant, compatible donor. The arrows indicate the places of cell transplantation. A drawing from an article in Nature Communications.
Nevertheless, six months later, scientists found immune cells in the brain tissues of macaques. At the same time, six months after the transplant from a compatible donor, there were about the same number of them as three months after the transplant from an incompatible one. According to the researchers, this is the first sign of tissue rejection.
Thus, compatibility with the donor did not allow to avoid rejection, but only to postpone its beginning. Perhaps it was caused not by MHC proteins, but by some other proteins on the cell surface (they are called minor antigens). Anyway, this result calls into question the use of therapy with foreign stem cells in humans. Apparently, it will not work without suppression of immunity; suppression of immunity, in turn, is fraught with the development of tumors.
Meanwhile, reprogrammed stem cells are gradually penetrating into the clinical field. In 2018, they were allowed to be tested in the treatment of a heart attack and began clinical trials against Parkinson's disease, and in 2019, the first patient received the cornea grown from them.
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