Gene variant is associated with higher risk of chronic rejection after lung transplant

Gene variant is associated with higher risk of chronic rejection after lung transplant

About a third of lung transplant recipients have a genetic variant that increases the likelihood of developing chronic lung allograft dysfunction (CLAD), the leading cause of death after lung transplantation. However, it is unclear why some lung transplant recipients develop CLAD and others do not. A study conducted by UCLA Health found that the cause may be a variant in the C3 gene that makes it difficult for the body to regulate the complement system, the part of the immune system that helps the body detect and eliminate infections and debris, such as those found in the transplanted lung.

“Lung transplantation has the worst long-term survival rate of any organ transplant, and this is largely due to chronic rejection,” said Dr. He is also the corresponding author of the study, published inThe Journal of Clinical Investigation.

“We wanted to understand why certain patients are more susceptible to chronic lung organ rejection than others and uncover new biological pathways that could lead to more effective therapies and ultimately better long-term outcomes for our patients.”

The study analyzed two separate cohorts of lung transplant recipients and found that about a third carried the C3 gene variant. In both groups, chronic rejection was more common in patients with this variant, particularly if they also had antibodies to the donor lung. To understand why, the researchers used a mouse lung transplant model with a similar predisposition to impaired complement regulation. These experiments showed that lung rejection was caused by the complement system activating certain B cells to produce antibodies that attack the transplanted lung - a process that current anti-rejection drugs cannot fully control.

We hope these findings will pave the way for new, more personalized therapies for chronic lung rejection, a disease for which there is currently no cure.”

Dr. Hrish Kulkarni, Associate Professor, Department of Pulmonary, Critical Care and Sleep Medicine, David Geffen School of Medicine

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