The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation · 2026
Beyond Donor-Specific Antibodies: Molecular Characterization of Antibody-Mediated Rejection Using Tissue-Based Transcriptomics in Heart Transplantation.
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Fernandez Valledor Andrea, Baranowska Julia, Hertz Adi, Moeller Cathrine M, Rahman Salwa, Oren Daniel, Bae David, Farrero Marta, Alvarez Ana Garcia, Lotan Dor, Fried Justin, Raihkelhar Jayant, DeFilippis Ersilia M, Takeda Koji, Latif Farhana, Majure David T, Clerkin Kevin J, Sayer Gabriel T, Uriel Nir
Аннотация
BACKGROUND: Antibody-mediated rejection (AMR) contributes to graft dysfunction after heart transplantation, yet histopathology and circulating donor-specific antibodies (DSA) may incompletely capture intragraft biology. We characterized molecular ABMR by human leukocyte antigen (HLA)-DSA status and, within DSA-negative cases, non-HLA antibody status.
METHODS: We analyzed 579 for-cause endomyocardial biopsies with paired Molecular Microscope Diagnostic System (MMDx) and histopathology. Molecular scores, transcripts, donor-derived cell-free DNA (dd-cfDNA), and gene-expression profiling (GEP) were compared using patient-clustered models with false-discovery-rate correction. Multivariable Cox models evaluated a 2-year composite of death, retransplantation, graft dysfunction (LVEF < 50%), or subsequent histologic rejection (acute cellular rejection [ACR] ≥ 1B/2R or pAMR ≥ 1).
RESULTS: MMDx-defined ABMR was present in 83 biopsies (14.3%); 30 (36.1%) were DSA-negative. DSA-negative and DSA-positive ABMR had similar ABMR probabilities (0.66 vs 0.66), global rejection scores, dd-cfDNA (0.83% vs 0.63%), GEP (35 vs 33), and transcriptomic profiles. Within DSA-negative ABMR, non-HLA antibodies were detected in 20/30 (66.7%) and associated with higher ABMR probability (0.69 vs 0.63; p = 0.041), dd-cfDNA (0.91% vs 0.62%; p = 0.048), GEP (35 vs 33; p = 0.019), and greater endothelial, ABMR/NK-cell, interferon-γ, and injury-related transcript activation. Histologic-molecular agreement was limited (κ = 0.14); 70/83 molecular ABMR biopsies lacked histologic pAMR. In joint models, molecular ABMR, but not pAMR, was associated with higher dd-cfDNA (b = 0.38%, p = 0.039). Conversely, histologic pAMR independently predicted the composite outcome (adjusted HR 2.68, 95% CI 1.34-5.35; p = 0.005), whereas molecular ABMR did not (adjusted HR 0.93, 95% CI 0.56-1.56; p = 0.795).
CONCLUSIONS: Molecular ABMR exhibited similar profiles regardless of HLA-DSA status. Non-HLA antibodies identified greater activation and dd-cfDNA levels within DSA-negative ABMR. Molecular assessment may complement conventional evaluation by refining ABMR phenotyping.
METHODS: We analyzed 579 for-cause endomyocardial biopsies with paired Molecular Microscope Diagnostic System (MMDx) and histopathology. Molecular scores, transcripts, donor-derived cell-free DNA (dd-cfDNA), and gene-expression profiling (GEP) were compared using patient-clustered models with false-discovery-rate correction. Multivariable Cox models evaluated a 2-year composite of death, retransplantation, graft dysfunction (LVEF < 50%), or subsequent histologic rejection (acute cellular rejection [ACR] ≥ 1B/2R or pAMR ≥ 1).
RESULTS: MMDx-defined ABMR was present in 83 biopsies (14.3%); 30 (36.1%) were DSA-negative. DSA-negative and DSA-positive ABMR had similar ABMR probabilities (0.66 vs 0.66), global rejection scores, dd-cfDNA (0.83% vs 0.63%), GEP (35 vs 33), and transcriptomic profiles. Within DSA-negative ABMR, non-HLA antibodies were detected in 20/30 (66.7%) and associated with higher ABMR probability (0.69 vs 0.63; p = 0.041), dd-cfDNA (0.91% vs 0.62%; p = 0.048), GEP (35 vs 33; p = 0.019), and greater endothelial, ABMR/NK-cell, interferon-γ, and injury-related transcript activation. Histologic-molecular agreement was limited (κ = 0.14); 70/83 molecular ABMR biopsies lacked histologic pAMR. In joint models, molecular ABMR, but not pAMR, was associated with higher dd-cfDNA (b = 0.38%, p = 0.039). Conversely, histologic pAMR independently predicted the composite outcome (adjusted HR 2.68, 95% CI 1.34-5.35; p = 0.005), whereas molecular ABMR did not (adjusted HR 0.93, 95% CI 0.56-1.56; p = 0.795).
CONCLUSIONS: Molecular ABMR exhibited similar profiles regardless of HLA-DSA status. Non-HLA antibodies identified greater activation and dd-cfDNA levels within DSA-negative ABMR. Molecular assessment may complement conventional evaluation by refining ABMR phenotyping.