A CD59 POLYMORPHISM IDENTIFIES PATIENTS AT RISK FOR CHRONIC REJECTION AFTER LUNG TRANSPLANTATION

Survival after lung transplantation is severely hampered by the development of the bronchiolitis obliterans syndrome (BOS), which is a manifestation of chronic rejection. As several autoand allo-antibodies are associated with BOS, we hypothesized that complement regulation within the allograft could contribute to BOS in the recipient. We sequenced and analyzed the promotor regions of membrane-bound complement regulatory proteins, CD46, CD55, and CD59.We identified a single SNP configuration in the promotor region of CD59 of the donor to be correlated with a higher incidence of BOS (p=0.032). Furthermore, we observed that primary endothelial cells derived from the lungs of donors having this SNP configuration display lower CD59 expression (p=0.016). Endothelial cells with this BOS-associated CD59-SNP generated more pro-fibrotic cytokines IL-6 and FGFb upon exposure to sublytical complement activation than cells from donors with the normal configuration (p=0.047, p=0.036 respectively). Monocytes from donors with the BOS-associated SNP configuration, but not lymphocytes, expressed less CD59 (p=0.013) and were more susceptible to antibody mediated complement lysis than cells from donors with the normal configuration (p<0.0001). We show that a SNP in the promoter region of CD59 leading to increased susceptibility of endothelial cells and monocytes to complement activation, carries a risk for the development of BOS after lung transplantation. These findings support a role for complement in the pathogenesis of this serious post-transplantation complication.