Donor HLA class 1 evolutionary divergence is a major predictor of liver allograft rejection: a retrospective cohort study

Abstract

AbstractBackgroundRecognition of donor antigens by the recipient’s immune system leads to allograft rejection. HLA evolutionary divergence (HED) between an individual’s HLA alleles is a continuous metric that quantifies the differences between each amino acid of two homologous alleles and reflects the breadth of the immunopeptidome presented to T lymphocytes. We investigated whether or not HED of the donor or of the recipient has an impact on liver transplant rejection.MethodWe did a retrospective cohort study in 1154 adult and 113 children recipients of liver transplant. We considered the histological lesions in liver biopsies performed routinely 1,2 and 5 years after transplantation and in case of liver dysfunction. Donor-specific anti-HLA antibodies (DSA) were determined in children at the time of biopsy. HED was calculated using the physicochemical Grantham distance for class I (HLA-A, HLA-B) and class II (HLA-DRB1, HLA-DQB1) alleles. We assessed the incidence of rejection-related liver lesions using a multivariate Cox proportional hazards regression analysis.FindingsIn the adult cohort, recipients from donors with class I HED above the median had a higher risk of acute or chronic rejection, but not of other histological lesions. HED of the recipients was not related to any histological lesion. In multivariate analysis, a high donor class I HED was associated with acute rejection (hazard ratio [HR] 1.79; 95% confidence interval [CI]: 1.34-2.40; P<0.0001) or chronic rejection (HR 2.26, CI 1.45-3.51; P<0.0001) and was independent of age and HLA identities. In the pediatric cohort, class I HED of the donor was also associated with acute rejection (HR 1.81, 95% CI 1.12-3.14; P=0.013) independently of the presence of DSA.InterpretationClass I HED of the donor reflects graft immunogenicity and predicts rejection independently of donor-recipient HLA compatibility. This novel and easily accessible prognostic marker could improve donor selection and guide immunosuppression.