C3d and the Septal Microvasculature as a Predictor of Chronic Lung Allograft Dysfunction

Studies have shown a potential role for humoral rejection in the evolution of lung graft dysfunction, apparently based on antibodies without human leukocyte antigen specificity. The correlation between extent of C4d deposition with clinical status further illustrates the importance of humoral immunity. Our study examines the potential value of C3d as a further diagnostic adjunct. C3d deposition was examined in lung allograft specimens using frozen tissue indirect direct immunofluorescence (IIF) and avidin biotin immunohistochemical applied to paraffin embedded tissue. Intermediate/extensive amounts of C3d using IIF and immunohistochemical (IH) methodologies correlated with chronic graft dysfunction; IIF C3d deposition was associated with septal and bronchial wall fibrosis (p < 0.0001). Weak/absent amounts of IIF and IH C3d correlated with clinical stability (p < 0.0001). Higher levels of C3d by IH were more sensitive than by IIF as a bronchiolitis obliterans syndrome determinant. C3d and C4d deposition using immunofluorescence and IH were correlated (p < 0.00001). C3d deposition appears prognostically significant. Higher tissue expression of C3d mark chronic graft dysfunction/persistent graft failure following transplantation. The close correlation between C3d and C4d lends credence to the role of humoral allograft rejection as a pulmonary graft dysfunction contributing factor. C3d by IH manifests higher sensitivity but similar specificity compared to C3d by IIF.