Table of Contents
February 27, 2024
3 minute read
Important points:
- Immunosuppressive drugs prescribed to prevent kidney allograft rejection in humans can also be used in pig-to-human kidney transplants.
- Researchers have found that complement inhibitors help reduce rejection.
FDA-approved immunosuppressants used to prevent rejection after kidney transplants may be just as effective in pig-to-human transplants, especially if complement inhibitors are added to the regimen This is shown in published research.
“I think this study is very important because it helps define the optimal FDA-approved immunosuppressive therapy for pig-to-human transplants that mimics that used in human-to-human transplants. Because it’s helpful.” jamie E. rockmedical doctor, Professor of Surgery at the Marnix E. Hersink School of Medicine at the University of Alabama at Birmingham (UAB) and author of the study told Helio. “Many of the studies conducted in preclinical non-human primate xenotransplantation utilize immunosuppressive drug therapies that are not FDA-approved and not used in human-to-human transplantation; This is important,” Professor Locke said. “Therefore, it is important to identify regimens that we, as transplant physicians and surgeons, are already familiar with and that are effective in the pig-to-human transplant setting,” Locke said. “We are excited about how this will move the field forward.”
The results announced in the study are clinical research journal, These are the third set of xenograft findings by UAB surgeon-scientists since 2022. In each case, the research team used the Parsons model, a preclinical human research model developed by UAB in recipients who had experienced brain death. The model is named after Jim Parsons, an Alabama organ donor whose family donated his body to advance xenotransplant kidney research, according to a press release.
Allogeneic transplant failure
UAB researchers have successfully transplanted a genetically modified pig kidney into a human recipient after brain death. However, Locke told Helio that he had discovered an important finding that could lead to rejection of pig kidneys, called thrombotic microangiopathy (TMA).
“We sometimes see things like this from allograft to allograft in humans,” Professor Locke said. “When we see it early on, we think that perhaps the body is reacting negatively to the new transplant and it could be an early sign of rejection.
“We wanted to test this… and were concerned that the end result of this TMA reflected activation of the immune system, called the complement system,” Dr. Locke said. told.
According to the release, complement inhibitors can be used to fight the immune system, “forming membrane attack complexes that are microscopic battering rams that break through cellular defenses and ultimately cause organ failure.” That’s what it means.
Membrane attack complexes (MACs) “basically sit like little drills on the surface of cells and punch holes in them,” Locke told Healio. “If you punch a hole in a cell, it weakens and dies. If you kill enough cells, the tissue dies. If you destroy enough tissue, the organ dies. Complement inhibitors are , which prevents the formation of this drill on the cell surface. It’s like creating a force shield around the kidney.”
This complement inhibitor is already an FDA-approved regimen for patients with a rare kidney disease known as atypical hemolytic uremic syndrome.
result
In this study, complement inhibitors were used in two of three donor patients aged 53 to 65 or deceased who received xenotransplants of 10 gene-edited pig kidneys after bilateral native nephrectomy. Ta. The first recipient received standard immunosuppression.
“There was no evidence of hyperacute rejection in any of the deaths,” the authors wrote. “Decedent 2 and 3 received anti-C5 monoclonal antibody therapy (eculizumab) 24 hours before (1,200 mg) and 24 hours after (900 mg) xenotransplantation.”
Locke said a biopsy of the first deceased pig’s kidney on the first day of transplantation was histologically normal, but the new organ began to show signs of rejection the day after transplantation. There were no signs of rejection in the two decedents who received complement inhibitors.
“Although complement activation is difficult to decipher in the context of both brain death and xenotransplantation, C5 inhibition may be beneficial in preventing TMA in pig-to-human xenotransplantation,” Locke et al. wrote. ing. “However, although there was no evidence of complement activation in decedent 1’s native kidney, MAC deposition and TMA progressed rapidly after xenotransplantation, indicating that brain death was not a physiological phenomenon but rather an immune response to the xenograft.” was suggested.”
The study results are “great news,” Locke said in the release. “We now know that FDA-approved immunosuppressive therapies are already available, treatments that are known to be tolerated by patients and that transplant physicians are familiar with. It’s a treatment you already know how to use.
“This is another important piece that we hope will lead to FDA approval for Phase I clinical trials in live humans in the near future.”
collapse
Disclosure: Locke reports consulting fees from Sanofi, United Therapeutics, and its subsidiaries Revivicor and Lung Biotechnology. United Therapeutics awarded UAB a grant to start a xenotransplant program. Please see the study for relevant financial disclosures by other authors.
