Bold claim: a single gene variant may tilt the odds toward chronic rejection after a lung transplant. About one in three lung transplant recipients carry a genetic variant that heightens the risk of chronic lung allograft dysfunction (CLAD), the leading cause of death following lung transplantation. Yet the reason some patients progress to CLAD while others do not has remained unclear. A study led by UCLA Health points to a possible culprit: a variant in the C3 gene. This variant appears to impair the body’s ability to regulate the complement system, a component of the immune defense that helps identify infections and clear debris, including material in the transplanted lung.
Lung transplantation historically suffers from the poorest long-term survival among solid organ transplants, largely due to chronic rejection, noted Dr. Hrish Kulkarni, the Allan J. Swartz and Roslyn Holt Swartz Women’s Lung Health Endowed Chair and an associate professor in the Division of Pulmonary, Critical Care and Sleep Medicine at the David Geffen School of Medicine. He also served as the study’s corresponding author, with findings published in The Journal of Clinical Investigation.
The researchers aimed to understand why certain patients are more susceptible to chronic lung organ rejection and to identify biological pathways that could lead to safer, more effective therapies and better long-term outcomes for patients.
By examining two separate cohorts of lung transplant recipients, the team found that roughly one-third carried the C3 gene variant. In both groups, individuals with this variant were more prone to chronic rejection, particularly when they also possessed antibodies directed against the donor lungs. To delve into the mechanism, scientists employed a mouse model of lung transplantation with a similar tendency toward impaired complement regulation. The experiments revealed that rejection occurred when the complement system activated specific B cells to produce antibodies targeting the transplanted lung—a process not fully controlled by current anti-rejection medications.
“We hope these findings open the door to more personalized therapies for chronic lung rejection, a disease that, at present, has no cure,” Kulkarni remarked.
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