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-C expression levels to identify permissible HLA-C mismatches. The median fluorescence intensity, a proxy of HLA-C expression, was assigned to each HLA-C allotype in 1975 patients and their HLA-C-mismatched unrelated transplant donors. The association of outcome with the level of expression of patients' and donors' HLA-C allotypes was evaluated in multivariable 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 new information on mismatches that should be avoided and extend understanding of HLA-C-mediated immune responses in human disease.

Anthony Nolan Research Institute The Royal Free Hampstead NHS Trust London United Kingdom;

Cancer and Inflammation Program SAIC Frederick Inc Frederick National Laboratories for Cancer Research Frederick MD; and

Cancer and Inflammation Program SAIC Frederick Inc Frederick National Laboratories for Cancer Research Frederick MD; and Ragon Institute of the Massachusetts General Hospital Massachusetts Institute of Technology and Harvard University Boston MA

Cancer Care Manitoba University of Manitoba Winnipeg MB Canada;

Center for International Blood and Marrow Transplant Research Medical College of Wisconsin Milwaukee WI;

Center for International Blood and Marrow Transplant Research Minneapolis MN;

Cliniques St Luc Université Catholique de Louvain Brussels Belgium;

Department for Blood Group Serology and Transfusion Medicine Medical University of Vienna Vienna Austria;

Department of Clinical Immunology Royal Perth Hospital Perth Australia;

Department of Immunology Oslo University Hospital Oslo Norway;

Division of Clinical Research Fred Hutchinson Cancer Research Center Seattle WA;

Division of Clinical Research Fred Hutchinson Cancer Research Center Seattle WA; Department of Medicine University of Washington School of Medicine Seattle WA;

Division of Therapeutic Immunology Center for Allogeneic Stem Cell Transplantation Karolinska University Hospital Huddinge Sweden;

European Group for Blood and Marrow Transplantation and University of Perugia Perugia Italy;

Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino Genova Italy;

Laboratoire d'Histocompatibilité et d'Immunogénétique Etablissement Français du Sang Pays de Loire Nantes France;

Leiden University Medical Center and Europdonor Foundation Leiden The Netherlands;

Memorial Sloan Kettering Cancer Center New York NY;

National Reference Laboratory for Histocompatibility Department of Genetics and Laboratory Medicine University Hospital Geneva Geneva Switzerland;

Universitätsklinikum Carl Gustav Carus Dresden Germany;

University Hospital Pilsen Czech Republic;

University of Cape Town Cape Town and South African Bone Marrow Registry Cape Town South Africa;

Blood. 2014 Dec 18;124(26):3839-40. doi: 10.1182/blood-2014-10-607853. PubMed

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