HLA mismatches and hematopoietic cell transplantation: Structural simulations assess the impact of changes in peptide binding specificity on transplant outcome |
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Authors: | Yanover Chen Petersdorf Effie W Malkki Mari Gooley Ted Spellman Stephen Velardi Andrea Bardy Peter Madrigal Alejandro Bignon Jean-Denis Bradley Philip |
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Institution: | Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. |
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Abstract: | 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 effect 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 International 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. |
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