Genetic Clue Explains Lung Transplant Rejection Risk

Study identifies a C3 gene variant that impairs immune regulation and increases CLAD risk after lung transplantation.

Roughly one third of lung transplant recipients carry a genetic variant that increases their likelihood of developing chronic lung allograft dysfunction (CLAD), the leading cause of death after transplantation.

What drives this difference has been unclear, but new research indicates that a variation in the C3 gene may be responsible, as it reduces the body’s ability to properly regulate the complement system, which is essential for recognizing and clearing infections and debris in the transplanted lung. ().

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Lung Transplants Face the Poorest Long-Term Survival

“Lung transplantation has the poorest long-term survival of any solid organ transplant, and that’s largely because of 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 the Division of Pulmonary, Critical Care and Sleep Medicine at the David Geffen School of Medicine. He is also corresponding author of the study, published in The Journal of Clinical Investigation.

“We wanted to understand why certain patients are more vulnerable 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.”

Genetic Variant Identified Causing Chronic Lung Rejection

The study analyzed two separate cohorts of lung transplant recipients and found that about one-third carried the C3 gene variant. In both groups, patients with this variant were more likely to experience chronic rejection, especially if they also had antibodies against the donor lungs.

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To understand why, researchers used a mouse lung transplant model with a similar predisposition to impaired complement regulation.

These experiments showed that the lung rejection was caused by the complement system activating certain B cells to make antibodies that attack the transplanted lung – a process that current anti-rejection medicines cannot fully control.

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“We hope these findings pave the way for new, more personalized therapies for chronic lung rejection, a disease that currently has no cure,” Kulkarni said.

Reference:

Why do some lung transplant patients face higher rejection risk? - (https://www.uclahealth.org/news/release/why-do-some-lung-transplant-patients-face-higher-rejection)

Source-University of California - Los Angeles Health Sciences