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HLA mismatches and hematopoietic cell transplantation: structural simulations assess the impact of changes in pep-tide binding specificity on transplant outcome

Chen Yanover, Effie W. Petersdorf, Mari Malkki, Ted Gooley, Stephen Spellman, Andrea Velardi, Pe-ter Bardy, Alejandro Madrigal, Jean-Denis Bignon, Philip Bradley

The success of hematopoietic cell transplantation from an unrelated donor depends in part on the degree of Human Histocompatibility Leukocyte Antigen (HLA) matching between donor and patient. We present a structure-based analysis of HLA mismatching, focusing on individual amino acid mismatches and their ef-fect on peptide binding specificity. Using molecular modeling simulations of HLA-peptide interactions, we find evidence that amino acid mismatches predicted to perturb peptide binding specificity are associated with higher risk of mortality in a large and diverse dataset of patient-donor pairs assembled by the Interna-tional Histocompatibility Working Group in Hematopoietic Cell Transplantation consortium. This analysis may represent a first step toward sequence-based prediction of relative risk for HLA allele mismatches