Bold reality check: a genetic variant may be quietly steering some lung transplant patients toward chronic rejection, while others slip by unnoticed. And this is the part most people miss: a C3 gene variant could be a key driver behind chronic lung allograft dysfunction (CLAD), the leading cause of death after lung transplantation. New findings from UCLA Health suggest that impaired regulation of the complement system—the immune system’s cleanup crew for infections and debris—plays a pivotal role in this risk elevation.
Lung transplants are notorious for having the poorest long-term survival among solid organ transplants, largely due to chronic rejection. In this study, led by 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, researchers sought to understand why some patients are more vulnerable to ongoing rejection than others. The study, published in The Journal of Clinical Investigation, also aims to uncover new biological pathways that could inform more effective therapies and improve long-term outcomes.
The researchers analyzed two separate cohorts of lung transplant recipients and found that roughly one-third carried the C3 gene variant. In both cohorts, individuals with this variant were more prone to chronic rejection, particularly if they also possessed antibodies against the donor lungs. To probe the mechanism, scientists used a mouse lung transplant model with a similar defect in complement regulation. The results showed that rejection was driven by the complement system activating certain B cells to produce antibodies that attack the transplanted lung—a 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, a disease that currently has no cure,” Kulkarni stated.
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