Diagnostic significance of intragraft donor–specific anti-HLA antibodies in pulmonary antibody–mediated rejection

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BACKGROUND: The diagnosis of pulmonary antibody-mediated rejection (AMR) remains challenging with lack of specific defining features. This study evaluated the diagnostic and prognostic significance of intragraft anti human leukocyte antigen (HLA) donor-specific antibodies (gDSA) in pulmonary AMR. METHODS: This multicenter prospective study enrolled adult lung transplant recipients (LTR) with serum anti-HLA DSA (sDSA) >1,000 Luminex mean fluorescence intensity (MFI). Transbronchial biopsies (TBBx) were obtained for both standard histologic analysis and cryopreservation to detect anti-HLA class I and II gDSA, using Luminex single-antigen beads assay. Clinical follow-up was conducted over 24 months. An expert pathologist reviewed all TBBx using a predefined checklist. A blinded adjudication panel categorized clinical diagnoses as possible, probable, or definite AMR and non-AMR conditions. The primary objective was to assess gDSA sensitivity and specificity for AMR diagnosis. Additionally, we compared graft outcomes between gDSA+ vs gDSA- patients. RESULTS: Seventy-seven LTR from 5 centers were included from August 2019 to July 2022. Twenty-nine patients were classified as probable or definite clinical/subclinical AMR. Among the cohort, 13 had positive gDSA. gDSA sensitivity, specificity, and positive predictive value for AMR diagnosis were 34.4%, 93.7%, and 76.9%, respectively. gDSA diagnostic performance for AMR was better than sDSA ≥12,500 MFI (sensitivity 37.9%, specificity 85.4%, and positive predictive value 61.1%). Event-free survival analysis (10% forced expiratory volume in 1 second decline or graft loss) showed no significant differences by gDSA positivity. Limited biopsy sampling and spatial heterogeneity may have biased sensitivity and prognostic performances of the technique. CONCLUSIONS: gDSA might offer a specific complementary support for the clinical diagnosis of AMR following lung transplantation.

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