Transplanting a genetically modified pig kidney to a brain-dead patient for two months allowed for a detailed “map” of the immune response, which may contribute to improving the results of future clinical trials and better understanding the causes of xenotransplant failure.
The results are presented in two investigations published in the journal Nature. The first focused on physiological studies and the second on the human response to the animal organ from an immunological point of view.
One of the questions was to know if this genetically modified organ can reproduce the physiological and functional activities of a human being and, therefore, serve effectively as a substitute.
“The good news is that the answer seems to be yes,” researcher Robert Montgomery, of the New York University Langone Transplant Institute and signatory of one of the articles.
He genetically modified pig kidney transplantalong with a treatment to suppress the immune response, has so far shown promising results. However, the response that leads to rejection is not fully understood, as studies analyzing that process have been limited to short periods.
During the two months of the current study, The researchers faced two situations of organ rejection, the first at 33 days, although “complete reversal” was achieved and without damaging the organ.something that is the first time that has been achieved in a xenotransplantation, he added.
The “unusual” thing about this case is that they were able to monitor the xenotransplantation for two months, performed on a 57-year-old brain-dead patient, with a functioning heart and assisted breathing, said the researcher.
This allowed blood, tissue and body fluid collections to be performed at a rate that cannot be safely performed in living patients or in primate trials. “I think,” he indicated, “that I could be the most studied human being in history.”
Rejection episodes
In this way, it was possible to trace the network of interactions that occur between immune cells when a porcine organ is tolerated by a human being and when it suffers an episode of rejection.
The results “better prepare us” to anticipate and address harmful immune reactions, laying the groundwork for more successful clinical trials in the “near future.”
The researchers discovered that the rejection episodes were caused by antibodies (immune proteins that “mark” foreign substances for subsequent destruction) and by T cells, which attack and destroy specific invaders.
Montgomery reiterated the importance of maintaining the study for two months, to be able to observe the adaptive immune response. Rejection episodes are known to occur and “we are very good at managing” those that occur in transplants between people, but “we did not know what it would be like in a xenotransplant” and “we were able to completely reverse it.”
The team measured the levels of various blood biomarkers, which show promise as an early warning system for porcine organ rejection.
The specific immune reactions revealed in the research provide “clear targets” for therapies that improve the success of xenotransplantations and address “the serious shortage of available organs,” highlighted Brendan Keating, from the New York Grossman School of Medicine and one of the signatories of the second article.
Minimalist gene editing
For the trial, a “very minimalist” genetic editing of the kidney was used, only of the alpha-gal gene, present in porcine organs and which causes immediate rejection when transplanted into human beings. After two months, it was still working well and without any major problems.
In addition, part of the animal’s thymus, which is the organ that educates the immune system, was transplanted, as previous studies by the team had indicated that it reduces the immune attack on the donated organ, an approach that seemed to work in this case.
Montgomery highlighted the importance of these studies with which it is known that when a pig kidney is implanted in a person “it is capable of “doing most of the things that a human kidney does”.
In the case of things it doesn’t do, “either we have redundancy and we don’t necessarily need it, or there are some medications that we need to supplement. Other than that, we’re ready to move forward” with research, he says.