Bold claim: one genetic variant can tilt the odds toward chronic rejection after a lung transplant. In fact, about one in three lung transplant recipients carries a specific gene variant that raises the risk of chronic lung allograft dysfunction (CLAD), the leading cause of death after these transplants. 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 possible driver. This variant appears to hinder how effectively the body regulates the complement system, a component of the immune response that helps detect infections and clear debris, including damaged tissue in the transplanted lung.
Lung transplantation is notorious for having the poorest long-term survival among solid organ transplants, a challenge largely driven by chronic rejection, notes 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 is the study’s corresponding author, and the research was published in The Journal of Clinical Investigation.
The researchers aimed to understand why certain patients are more susceptible to chronic lung rejection and to identify biological pathways that could lead to better therapies and, ultimately, improved long-term outcomes. The team examined two separate cohorts of lung transplant recipients and found that roughly one-third carried the C3 gene variant. In both cohorts, carriers faced a higher likelihood of chronic rejection, particularly when they also had donor-specific antibodies.
To probe the mechanism, the scientists used a mouse lung transplant model with a similar tendency toward impaired complement regulation. The experiments revealed that rejection was driven by the complement system activating particular B cells to produce antibodies that attack the transplanted lung—an immune process not fully controlled by current anti-rejection drugs.
“We hope these findings pave the way for new, more personalized therapies for chronic lung rejection—an ailment that currently has no cure,” Kulkarni said.
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