title: 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: H. Lee Moffitt Cancer Center, Tampa, FL;
authors: Joseph
authors: J
authors: Pidala
authors: Tao
authors: T
authors: Wang
authors: Michael
authors: M
authors: Haagenson
authors: Stephen R
authors: SR
authors: Spellman
authors: Medhat
authors: M
authors: Askar
authors: Minoo
authors: M
authors: Battiwalla
authors: Lee Ann
authors: LA
authors: Baxter-Lowe
authors: Menachem
authors: M
authors: Bitan
authors: Marcelo
authors: M
authors: Fernandez-Viña
authors: Manish
authors: M
authors: Gandhi
authors: Ann A
authors: AA
authors: Jakubowski
authors: Martin
authors: M
authors: Maiers
authors: Susana R
authors: SR
authors: Marino
authors: Steven G E
authors: SG
authors: Marsh
authors: Machteld
authors: M
authors: Oudshoorn
authors: Jeanne
authors: J
authors: Palmer
authors: Vinod K
authors: VK
authors: Prasad
authors: Vijay
authors: V
authors: Reddy
authors: Olle
authors: O
authors: Ringden
authors: Wael
authors: W
authors: Saber
authors: Stella
authors: S
authors: Santarone
authors: Kirk R
authors: KR
authors: Schultz
authors: Michelle
authors: M
authors: Setterholm
authors: Elizabeth
authors: E
authors: Trachtenberg
authors: E Victoria
authors: EV
authors: Turner
authors: Ann E
authors: AE
authors: Woolfrey
authors: Stephanie J
authors: SJ
authors: Lee
authors: Claudio
authors: C
authors: Anasetti
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D064591:Allografts; D019943:Amino Acid Substitution; D001665:Binding Sites / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology* / Q000235:genetics / Q000401:mortality; D015236:HLA-C Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000401:mortality; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D054340:Receptors, KIR / Q000378:metabolism; D012307:Risk Factors; D014019:Tissue Donors
chemical_list: D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; D054340:Receptors, KIR
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