A new UCLA Health–led study has identified a genetic explanation for why some lung transplant recipients are more prone to chronic lung allograft dysfunction (CLAD), the leading cause of long-term mortality after lung transplantation. Roughly one-third of patients carry a variant of the C3 gene that appears to impair regulation of the complement system—an essential component of the immune response responsible for clearing infections and debris from tissues, including transplanted lungs.
“Lung transplantation has the lowest long-term survival among all solid organ transplants, primarily due to chronic rejection,” said Dr. Hrish Kulkarni, the Allan J. Swartz and Roslyn Holt Swartz Women’s Lung Health Endowed Chair and associate professor in the Division of Pulmonary, Critical Care and Sleep Medicine at the David Geffen School of Medicine. Kulkarni is the corresponding author of the study, published in The Journal of Clinical Investigation.
“Our goal was to understand why some patients are more susceptible to chronic lung rejection and to uncover biological pathways that could help guide improved therapies and long-term outcomes.”
Researchers analyzed two independent cohorts of lung transplant recipients and found that individuals carrying the C3 variant had a significantly higher risk of developing CLAD—especially when donor-specific antibodies were present. In complementary mouse models exhibiting similar complement-regulation defects, the team discovered that complement activation stimulated B cells to produce antibodies that attack the transplanted lung, a mechanism not fully controlled by current anti-rejection therapies.
“These findings may open the door to more personalized strategies for preventing and treating chronic lung rejection—a condition for which no cure currently exists,” Kulkarni said.
