HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation

Life-threatening graft-versus-host disease (GVHD) limits the use of HLA-C-mismatched unrelated donors in transplantation. Clinicians lack criteria for donor selection when HLA-C-mismatched donors are a patient's only option for cure. We examined the role for HLA-Cexpressionlevels to identify permissible HLA-Cmismatches.Themedian fluorescence intensity, a proxy of HLA-Cexpression,was assigned to each HLA-C allotype in 1975 patients and their HLA-C-mismatched unrelated transplant donors. The association of outcome with the levelofexpressionof patients'anddonors'HLA-Callotypeswasevaluated inmultivariable models. Increasing expression level of the patient's mismatched HLA-C allotype was associated with increased risks of grades III to IV acute GVHD, nonrelapse mortality, and mortality. Increasing expression level among HLA-C mismatches with residue 116 or residue 77/80 mismatching was associated with increased nonrelapse mortality. The immunogenicity of HLA-C mismatches in unrelated donor transplantation is influenced by the expression level of the patient's mismatched HLA-C allotype. HLA-C expression levels provide newinformation onmismatches that should be avoided and extend understanding of HLA-C-mediated immune responses in human disease.