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

Publication Type:

Journal Article

Source:

Blood (2013)

Keywords:

2013, Clinical Research Division, September 2013

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 KIR binding position 77 of HLA-A, B, or C, on the risks for grade III-IV 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 (HR 1.45, 95% CI 1.15-1.82, p = 0.0016). Mismatch at HLA-C position 99 was associated with increased transplant-related mortality (HR 1.37, 95% CI 1.1-1.69, p = 0.0038). Mismatch at HLA-B position 9 was associated with increased chronic GVHD (HR 2.28, 95% CI 1.36-3.82, p = 0.0018). No AAS were significantly associated with outcome at HLA-A. Specific AAS pair combinations with frequency > 30 were tested for association with HCT outcomes. Cysteine -> tyrosine substitution at position 99 of HLA-C was associated with increased TRM (HR 1.78, 95% CI 1.27-2.51, p=0.0009). 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.