HLA-DQ molecular mismatch predicts acute rejection and donor-specific antibody development after pediatric liver transplantation

Background Prediction 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. Methods A 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). Results During 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). Conclusions We 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.