The C3 variant appears to disrupt regulation of the complement system, contributing to chronic rejection of transplanted lungs.

Overall, the study identifies a genetic basis for differential rejection risk and highlights the complement activation pathway as a potential target for new therapies.

Donor-specific antibodies play a key role in the observed rejection dynamics.

Mouse lung transplant experiments with similar complement-regulation deficits show that complement activation drives B cells to produce antibodies that attack the graft, a mechanism not fully controlled by current anti-rejection treatments.

The study reports that about one-third of lung transplant recipients carry the C3 gene variant associated with higher CLAD risk.

Senior author Dr. Hrish Kulkarni notes these findings could lead to targeted therapies for chronic lung rejection, which currently lacks a cure.

A UCLA Health-led study finds that impaired regulation of the complement system drives chronic lung allograft dysfunction and could pave the way for personalized therapies to improve long-term outcomes for lung transplant recipients.

The risk rises when the genetic variant is present alongside donor-specific antibodies against the transplanted lungs.

In two independent cohorts, recipients with the C3 variant showed a higher likelihood of CLAD, especially if they carried antibodies against donor lungs.

The research is published in The Journal of Clinical Investigation in 2025, with DOI 10.1172/jci188891.