A critical genetic mismatch may influence kidney transplant success and could inform how donor-recipient compatibility is assessed, according to a study published in Science Translational Medicine.
For decades, transplant medicine has focused on matching human leukocyte antigens (HLA)— unique proteins that assist the immune system in distinguishing itself from invading cells or disease. But the new research reveals that a mismatch within the innate immune system itself may also play a pivotal role in transplant rejection and long-term survival.
“The major impediment to long-term survival of transplanted organs is the production of antibodies against donor-specific HLA markers,” said Anat Roitberg-Tambur, DMD, PhD, research professor of Surgery in the Division of Organ Transplantation and co-author of the study. “But our immune system also has innate mechanisms of defense, and we wanted to explore whether these could also contribute to transplant rejection.”
In the current study, scientists focused on signal regulatory protein a (SIRPa), a molecule on immune cells that interacts with CD47, a so-called “don’t eat me” signal expressed on many cell types. In mouse models, they found that mismatches in SIRPa variants activated immune “fighter” cells, leading to inflammation and chronic kidney damage. When the SIRPa-CD47 interaction was blocked, however, this damage was prevented.
Next, investigators analyzed data from 455 kidney transplant recipients enrolled in previous scientific studies. They found that SIRPa mismatch was linked to increased rejection and fibrosis within the first year. Long-term survival was also significantly reduced, with a 3.2-fold higher risk of transplant failure. These findings were confirmed in a second, independent cohort of 258 patients.
“The current study validated our original observation that a specific mismatch direction —when a recipient with SIRPa haplotype A receives a kidney from a donor with haplotype B —leads to worse transplant outcomes,” Tambur said. “This directionality was confirmed in additional human cohorts and explained by mouse experiments showing greater monocyte activation in this mismatch scenario.”
Tambur anticipates that these findings will inspire a multi-center clinical trial to test whether SIRPa can be used to guide transplant decisions.
“This is a new frontier in transplant immunology,” Tambur said. “Exploring how innate immune mismatches shape transplant outcomes can help prolong the lifespan of these precious life-saving organs.”
The study was supported by National Institutes of Health grants AI099465, AI172973 and AI181954. Grants from the Société Francophone de Transplantation, the Assistance Publique des Hôpitaux de Paris and the Philippe Foundation provided additional funding.
