Donor HLA Class 1 Evolutionary Divergence Is a Major Predictor of Liver Allograft Rejection
Cyrille Féray, Jean‐Luc Taupin, Mylène Sebagh, Vincent Allain, Zeynep Demir, Marc‐Antoine Allard, Christophe Desterke, Audrey Coilly, Faouzi Saliba, Éric Vibert, Daniel Azoulay, Catherine Guettier, Arthur Chatton, Dominique Debray, Sophie Caillat‐Zucman, Didier Samuel
Abstract
Background: The HLA evolutionary divergence (HED), a continuous metric quantifying the peptidic differences between 2 homologous HLA alleles, reflects the breadth of the immunopeptidome presented to T lymphocytes. Objective: To assess the potential effect of donor or recipient HED on liver transplant rejection. Design: Retrospective cohort study. Setting: Liver transplant units. Patients: 1154 adults and 113 children who had a liver transplant between 2004 and 2018. Measurements: Liver biopsies were done 1, 2, 5, and 10 years after the transplant and in case of liver dysfunction. Donor-specific anti-HLA antibodies (DSAs) were measured in children at the time of biopsy. The HED was calculated using the physicochemical Grantham distance for class I (HLA-A or HLA-B) and class II (HLA-DRB1 or HLA-DQB1) alleles. The influence of HED on the incidence of liver lesions was analyzed through the inverse probability weighting approach based on covariate balancing, generalized propensity scores. Results: In adults, class I HED of the donor was associated with acute rejection (hazard ratio [HR], 1.09 [95% CI, 1.03 to 1.16]), chronic rejection (HR, 1.20 [CI, 1.10 to 1.31]), and ductopenia of 50% or more (HR, 1.33 [CI, 1.09 to 1.62]) but not with other histologic lesions. In children, class I HED of the donor was also associated with acute rejection (HR, 1.16 [CI, 1.03 to 1.30]) independent of the presence of DSAs. There was no effect of either donor class II HED or recipient class I or class II HED on the incidence of liver lesions in adults and children. Limitation: The DSAs were measured only in children. Conclusion: Class I HED of the donor predicts acute or chronic rejection of liver transplant. This novel and accessible prognostic marker could orientate donor selection and guide immunosuppression. Primary Funding Source: Institut National de la Santé et de la Recherche Médicale.