HLA mismatches and hematopoietic cell transplantation: structural simulations assess the impact of changes in peptide binding specificity on transplant outcome.
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.
Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Chen
C
Yanover
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Effie W
EW
Petersdorf
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Mari
M
Malkki
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Ted
T
Gooley
Center for International Blood and Marrow Transplant Research, USA.
Stephen
S
Spellman
European Group for Blood and Marrow Transplantation, Italy.
Andrea
A
Velardi
Australian Bone Marrow Donor Registry, Australia.
Peter
P
Bardy
Anthony Nolan, UK.
Alejandro
A
Madrigal
Blood Bank Nantes and SFGM, France.
Jean-Denis
JD
Bignon
Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Philip
P
Bradley