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

Chen Yanover

doi:10.4172/1745-7580.1000048

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.

Highlights

Unrelated hematopoietic cell transplantations (HCTs) involving perfectly matched patientdonor pairs generally have higher success rates than those between patients and donors mismatched at one or more loci [1,2,3,4]
We investigate the connection between Histocompatibility Leukocyte Antigen (HLA) mismatching and transplant outcome, using structural predictions of HLApeptide interactions to characterize the impact of amino acid mismatches on peptide binding specificity divergence, a potential mediator of T-cell alloreactivity
Using a large and diverse clinical dataset assembled by the International Histocompatibility Working Group in Hematopoietic Cell Transplantation consortium, we find support for the hypothesis that residue-level mismatches predicted by structural modeling to perturb HLA-peptide binding specificity are associated with increased mortality risk

Summary

Introduction

Unrelated hematopoietic cell transplantations (HCTs) involving perfectly matched patientdonor pairs generally have higher success rates than those between patients and donors mismatched at one or more loci [1,2,3,4]. Knowledge of general patterns at the level of amino acid mismatches could allow estimation of risk even for allelelevel mismatches with insufficient prior clinical data. We investigate the connection between HLA mismatching and transplant outcome, using structural predictions of HLApeptide interactions to characterize the impact of amino acid mismatches on peptide binding specificity divergence, a potential mediator of T-cell alloreactivity. Using a large and diverse clinical dataset assembled by the International Histocompatibility Working Group in Hematopoietic Cell Transplantation consortium, we find support for the hypothesis that residue-level mismatches predicted by structural modeling to perturb HLA-peptide binding specificity are associated with increased mortality risk

Methods

Results

Conclusion