HLA-DQ molecular mismatch predicts acute rejection and donor-specific antibody development after pediatric liver transplantation
Abstract
BackgroundPrediction of alloimmune complications remains an unmet need in pediatric liver transplantation (PLT). Although HLA molecular mismatch (MM) has emerged as a promising biomarker in other solid organ transplants, current approaches rely on MM load, assuming that all MMs contribute equally to alloimmune risk. We aimed to evaluate the predictive value of MM, together with clinical and biochemical covariates, for biopsy-proven acute rejection (BPAR) and the development of de novo donor-specific antibodies (dnDSA) after PLT, and to assess the immunogenicity of individual MM units.MethodsA prospective cohort of 114 PLT recipients underwent high-resolution donor and recipient HLA typing. Clinical and MM-derived variables were evaluated as independent predictors using Cox proportional hazards models. Different MM approaches were evaluated, including individual HLA-DQ eplets and Snow-derived peptides, each encoded as a binary MM unit. Patient follow-up included surveillance and for-cause biopsies, together with dnDSA monitoring. Ridge-penalized Cox regression models were used to estimate the relative immunogenic contribution of each MM unit and to construct the outcome-specific epitope risk scores (BPAR-ERS and dnDSA-ERS).ResultsDuring follow-up, 67% and 32% of patients developed BPAR and dnDSA, respectively. HLA-DQ MM was significantly associated with both outcomes, although BPAR occurred significantly earlier than the first dnDSA detection (median [range], 0.97 [0.08-5.66] vs. 2.50 [0.78-5.50] years post-transplant; p<0.0001). Because HLA-DQ-specific dnDSA (dnDQ-DSA) was the predominant antibody specificity, subsequent analyses focused on this outcome. The eplet-derived BPAR-DQ-ERS and dnDQ-DSA-ERS outperformed conventional HLA-DQ eplet mismatch burden in predicting their respective outcomes. Patients in the highest ERS tertile exhibited significantly lower BPAR-free and dnDQ-DSA-free survival than those in the lower tertiles (both log-rank p<0.0001). In multivariable Cox regression analyses, BPAR-DQ-ERS (HR, 12.8; 95% CI, 5.0-33.0; p<0.0001) and variability in tacrolimus levels (HR, 4.5; 95% CI, 2.1-9.4; p<0.0001) were identified as independent predictors of BPAR. Independent predictors of dnDQ-DSA development were dnDQ-DSA-ERS (HR, 7.0; 95% CI, 3.3-14.8; p<0.0001) and previous BPAR (HR, 3.0; 95% CI, 1.1-8.1; p=0.0323).ConclusionsWe identified HLA-DQ MM as an independent predictor of BPAR and dnDQ-DSA development. Importantly, the relative immunogenic contribution of each MM unit should be considered when personalizing post-transplant immunosuppression and PLT management.
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BibTeX
@article{renatti2026hladq,
title = {{HLA-DQ molecular mismatch predicts acute rejection and donor-specific antibody development after pediatric liver transplantation}},
author = {Guido Trezeguet Renatti and Cecilia Gamba and Agostina Arrigone and Daniela Fernandez Souto and Julia Minetto and María Fernanda Yaunguzian and Gabriela Aboud and Florencia Degrave and Santiago Cervio and Hayellen Reijenstein and Agustina Jacobo Dillon and Diego Aredes and Leandro Lauferman and Ivone Malla and Stefania Conde and Cecilia Delfino and Natalia Riva and Marcelo Dip and Oscar Imventarza and Pablo Galarza and Esteban Halac and Paula Schaiquevich},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1996061},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1996061},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - HLA-DQ molecular mismatch predicts acute rejection and donor-specific antibody development after pediatric liver transplantation
AU - Guido Trezeguet Renatti
AU - Cecilia Gamba
AU - Agostina Arrigone
AU - Daniela Fernandez Souto
AU - Julia Minetto
AU - María Fernanda Yaunguzian
AU - Gabriela Aboud
AU - Florencia Degrave
AU - Santiago Cervio
AU - Hayellen Reijenstein
AU - Agustina Jacobo Dillon
AU - Diego Aredes
AU - Leandro Lauferman
AU - Ivone Malla
AU - Stefania Conde
AU - Cecilia Delfino
AU - Natalia Riva
AU - Marcelo Dip
AU - Oscar Imventarza
AU - Pablo Galarza
AU - Esteban Halac
AU - Paula Schaiquevich
PY - 2026
DA - 2026/11/02
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1996061
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1996061
AB - BackgroundPrediction of alloimmune complications remains an unmet need in pediatric liver transplantation (PLT). Although HLA molecular mismatch (MM) has emerged as a promising biomarker in other solid organ transplants, current approaches rely on MM load, assuming that all MMs contribute equally to alloimmune risk. We aimed to evaluate the predictive value of MM, together with clinical and biochemical covariates, for biopsy-proven acute rejection (BPAR) and the development of de novo donor-specific antibodies (dnDSA) after PLT, and to assess the immunogenicity of individual MM units.MethodsA prospective cohort of 114 PLT recipients underwent high-resolution donor and recipient HLA typing. Clinical and MM-derived variables were evaluated as independent predictors using Cox proportional hazards models. Different MM approaches were evaluated, including individual HLA-DQ eplets and Snow-derived peptides, each encoded as a binary MM unit. Patient follow-up included surveillance and for-cause biopsies, together with dnDSA monitoring. Ridge-penalized Cox regression models were used to estimate the relative immunogenic contribution of each MM unit and to construct the outcome-specific epitope risk scores (BPAR-ERS and dnDSA-ERS).ResultsDuring follow-up, 67% and 32% of patients developed BPAR and dnDSA, respectively. HLA-DQ MM was significantly associated with both outcomes, although BPAR occurred significantly earlier than the first dnDSA detection (median [range], 0.97 [0.08-5.66] vs. 2.50 [0.78-5.50] years post-transplant; p<0.0001). Because HLA-DQ-specific dnDSA (dnDQ-DSA) was the predominant antibody specificity, subsequent analyses focused on this outcome. The eplet-derived BPAR-DQ-ERS and dnDQ-DSA-ERS outperformed conventional HLA-DQ eplet mismatch burden in predicting their respective outcomes. Patients in the highest ERS tertile exhibited significantly lower BPAR-free and dnDQ-DSA-free survival than those in the lower tertiles (both log-rank p<0.0001). In multivariable Cox regression analyses, BPAR-DQ-ERS (HR, 12.8; 95% CI, 5.0-33.0; p<0.0001) and variability in tacrolimus levels (HR, 4.5; 95% CI, 2.1-9.4; p<0.0001) were identified as independent predictors of BPAR. Independent predictors of dnDQ-DSA development were dnDQ-DSA-ERS (HR, 7.0; 95% CI, 3.3-14.8; p<0.0001) and previous BPAR (HR, 3.0; 95% CI, 1.1-8.1; p=0.0323).ConclusionsWe identified HLA-DQ MM as an independent predictor of BPAR and dnDQ-DSA development. Importantly, the relative immunogenic contribution of each MM unit should be considered when personalizing post-transplant immunosuppression and PLT management.
SN - 1664-3224
ER -