Faculty Collaboration Database

Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality. Blood 2013 Nov 21;122(22):3651-8

Date

08/29/2013

Pubmed ID

23982174

Pubmed Central ID

PMC3837514

DOI

10.1182/blood-2013-05-501510

Scopus ID

2-s2.0-84888269622 (requires institutional sign-in at Scopus site)   72 Citations

Abstract

HLA disparity has a negative impact on the outcomes of hematopoietic cell transplantation (HCT). We studied the independent impact of amino acid substitution (AAS) at peptide-binding positions 9, 99, 116, and 156, and killer immunoglobulin-like receptor binding position 77 of HLA-A, B, or C, on the risks for grade 3-4 acute graft-versus-host disease (GVHD), chronic GVHD, treatment-related mortality (TRM), relapse, and overall survival. In multivariate analysis, a mismatch at HLA-C position 116 was associated with increased risk for severe acute GVHD (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.15-1.82, P = .0016). Mismatch at HLA-C position 99 was associated with increased transplant-related mortality (HR = 1.37, 95% CI = 1.1-1.69, P = .0038). Mismatch at HLA-B position 9 was associated with increased chronic GVHD (HR = 2.28, 95% CI = 1.36-3.82, P = .0018). No AAS were significantly associated with outcome at HLA-A. Specific AAS pair combinations with a frequency >30 were tested for association with HCT outcomes. Cysteine to tyrosine substitution at position 99 of HLA-C was associated with increased TRM (HR = 1.78, 95% = CI 1.27-2.51, P = .0009). These results demonstrate that donor-recipient mismatch for certain peptide-binding residues of the HLA class I molecule is associated with increased risk for acute and chronic GVHD and death.

Author List

Pidala J, Wang T, Haagenson M, Spellman SR, Askar M, Battiwalla M, Baxter-Lowe LA, Bitan M, Fernandez-Viña M, Gandhi M, Jakubowski AA, Maiers M, Marino SR, Marsh SG, Oudshoorn M, Palmer J, Prasad VK, Reddy V, Ringden O, Saber W, Santarone S, Schultz KR, Setterholm M, Trachtenberg E, Turner EV, Woolfrey AE, Lee SJ, Anasetti C

Authors

Wael Saber MD, MS Professor in the Medicine department at Medical College of Wisconsin
Tao Wang PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acute Disease
Adolescent
Adult
Aged
Allografts
Amino Acid Substitution
Binding Sites
Child
Child, Preschool
Female
Graft vs Host Disease
HLA-C Antigens
Hematopoietic Stem Cell Transplantation
Histocompatibility Antigens Class I
Histocompatibility Testing
Humans
Infant
Male
Middle Aged
Models, Molecular
Receptors, KIR
Risk Factors
Tissue Donors