C4d deposition in lung allografts is associated with circulating anti-HLA alloantibody

The complement activation demonstrated by vascular C4d deposition is used to diagnose antibody-mediated rejection (AMR) in renal allografts, but remains controversial in lung transplantation (LTX). Methods: C4d deposition was assessed by immunohistochemistry in 192 lung transplant biopsies from 32 patients. ELISA analysis was performed on 415 serum samples in those 32 temporally and rejection-grade matched LTX patients; 16 patients developed HLA-Ab, while the other 16 patients remained negative. The specificity of C4d staining was further compared in 18 additional LTX patients without HLA-Ab or acute cellular rejection (ACR), but in the presence of CMV-pneumonitis or reperfusion injury. Results: Specific subendothelial C4d deposition was seen in 5 of 16 (31%) patients with HLA-Ab and was absent in 16 patients without HLA-Ab (p<0.05). All patients with specific C4d deposition exhibited donor-specific HLA-Ab. There were 13 patients with bronchiolitis obliterans syndrome in the group of 16 HLA-Ab positive patients, versus 2/16 in ELISA-negative patients (p<0.005). One of 7 patients with CMV pneumonitis and 2 of 11 patients with reperfusion injury also showed C4d positivity (not statistically significant). Conclusions: In this study, specific subendothelial C4d deposition was a marker for the involvement of HLA-Ab in lung allograft rejection. The patchy, nature, low sensitivity, and specificity of C4d staining might limit clinical use in protocol biopsies. However, in patients with decreasing pulmonary function, refractory ACR and/or HLA-Ab, specific C4d deposition may serve as a marker of coexistent AMR. (c) 2005 Elsevier B.V All rights reserved.