Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality.

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.

• Authors: Joseph Pidala, Tao Wang, Michael Haagenson, Stephen R Spellman, Medhat Askar, Minoo Battiwalla, Lee Ann Baxter-Lowe, Menachem Bitan, Marcelo Fernandez-Viña, Manish Gandhi, Ann A Jakubowski, Martin Maiers, Susana R Marino, Steven G E Marsh, Machteld Oudshoorn, Jeanne Palmer, Vinod K Prasad, Vijay Reddy, Olle Ringden, Wael Saber, Stella Santarone, Kirk R Schultz, Michelle Setterholm, Elizabeth Trachtenberg, E Victoria Turner, Ann E Woolfrey, Stephanie J Lee, Claudio Anasetti
• Journal: Blood (Blood) Vol. 122 Issue 22 Pg. 3651-8 (Nov 21 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23982174 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• HLA-C Antigens
• Histocompatibility Antigens Class I
• Receptors, KIR

Topics

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