A genetic variant raises the risk of chronic rejection after a lung transplant
About one in three lung transplant recipients carries a genetic variant that heightens the chance of developing chronic lung allograft dysfunction (CLAD), the leading cause of mortality 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 variant in the C3 gene as a potential culprit. This variant appears to impair the body's ability to regulate the complement system, a component of the immune system that helps detect and remove infections and debris, including those that can accumulate in a transplanted lung.
“Lung transplants have the poorest long-term survival of any solid organ transplant, largely 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. He also serves as the study’s corresponding author, published in The Journal of Clinical Investigation.
“We aimed to understand why certain patients are more susceptible to chronic lung organ rejection and to identify new biological pathways that could lead to more effective therapies and, ultimately, better long-term outcomes for patients.”
In two separate cohorts of lung transplant recipients, researchers found that roughly one-third carried the C3 gene variant. Across both groups, those with the variant were more prone to chronic rejection, particularly if they also possessed antibodies against the donor lungs. To explore the mechanism, scientists used a mouse lung transplant model with a similar tendency toward impaired complement regulation. The experiments demonstrated that lung rejection occurred when the complement system activated specific B cells to produce antibodies that attack the transplanted lung—a process not fully controlled by current anti-rejection drugs.
“We hope these findings open the door to new, more personalized therapies for chronic lung rejection, a disease that currently has no cure,” Kulkarni said.
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