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DONOR-SPECIFIC ANTI-HLA ALLOANTIBODIES ARE ASSOCIATED WITH SUBENDOTHELIAL C4D DEPOSITION AND CHRONIC LUNG ALLOGRAFT DYSFUNCTION.
A. Girnita MD 1, D. Ionescu MD 1, S. Yousem MD 1, R. Duquesnoy PhD 1, K. Spichty BS 1, J. Pilewski MD 2, S. Studer MD 2, B. Johnson MD 2, K. McCurry MD 3 and A. Zeevi PhD 1. 1 Pathology, UPMC, Pittsburgh, PA ; 2 Medicine and 3 Surgery .
C4d is incorporated into the Banff scheme as a tissue marker for antibody-mediated rejection (AMR) in kidney allografts, but its association with anti-HLA alloantibodies (HLA-Ab) has not been documented in lung transplantation (LTX).
Methods: For 32 LTX patients, the C4d deposition was assessed by immunohistochemistry in 192 transbronchial biopsies (TBB), while HLA-Ab were detected by ELISA (415 serum samples). 16 patients exhibited post-LTX developed HLA-Ab, while other 16 - temporally and rejection-grade matched patients - remained negative.
Results: Specific linear, continuous, 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 C4d deposition exhibited donor-specific HLA-Ab. In 4/5 patients the C4d was identified in the period when circulating HLA-Ab were present, while in one patient C4d preceded the detection of HLA-Ab. The frequency of C4d deposition was: 4.7% in protocol+indication TBB, 21.5% in TBB showing high-grade acute rejection (HACR) and 33% in TBB from patients with HLA-Ab and HACR. Although the two groups exhibited the same prevalence of HACR, 13/16 patients ultimately developed chronic rejection in the ELISA-positive group, compared to only 2/16 in the ELISA-negative (p<0.005).
Conclusions: In this study, specific subendothelial C4d deposition was a marker for the involvement of HLA-Ab in lung allograft rejection. The patchy nature of C4d staining might limit clinical use in protocol biopsies. In patients with decreasing pulmonary function, HACR and/or HLA-Ab, specific C4d deposition may serve as a marker of coexistent AMR.