title: HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation.
abstract: 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.
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, University of Washington School of Medicine, Seattle, WA;
authors.forename: Effie W
authors.initials: EW
authors.lastname: Petersdorf
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Gooley
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Mari
authors.initials: M
authors.lastname: Malkki
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino, Genova, Italy;
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Bacigalupo
authors.affiliation: Laboratoire d'Histocompatibilité et d'Immunogénétique, Etablissement Français du Sang Pays de Loire, Nantes, France;
authors.forename: Anne
authors.initials: A
authors.lastname: Cesbron
authors.affiliation: University of Cape Town, Cape Town and South African Bone Marrow Registry, Cape Town, South Africa;
authors.forename: Ernette
authors.initials: E
authors.lastname: Du Toit
authors.affiliation: Universitätsklinikum Carl Gustav Carus, Dresden, Germany;
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.affiliation: Department of Immunology, Oslo University Hospital, Oslo, Norway;
authors.forename: Torstein
authors.initials: T
authors.lastname: Egeland
authors.affiliation: Department for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria;
authors.forename: Gottfried F
authors.initials: GF
authors.lastname: Fischer
authors.affiliation: Cliniques St. Luc, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Thibaut
authors.initials: T
authors.lastname: Gervais
authors.affiliation: Center for International Blood and Marrow Transplant Research, Minneapolis, MN;
authors.forename: Michael D
authors.initials: MD
authors.lastname: Haagenson
authors.affiliation: Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI;
authors.forename: Mary M
authors.initials: MM
authors.lastname: Horowitz
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Katharine
authors.initials: K
authors.lastname: Hsu
authors.affiliation: University Hospital, Pilsen, Czech Republic;
authors.forename: Pavel
authors.initials: P
authors.lastname: Jindra
authors.affiliation: Anthony Nolan Research Institute, The Royal Free Hampstead NHS Trust, London, United Kingdom;
authors.forename: Alejandro
authors.initials: A
authors.lastname: Madrigal
authors.affiliation: Leiden University Medical Center and Europdonor Foundation, Leiden, The Netherlands;
authors.forename: Machteld
authors.initials: M
authors.lastname: Oudshoorn
authors.affiliation: Division of Therapeutic Immunology, Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Huddinge, Sweden;
authors.forename: Olle
authors.initials: O
authors.lastname: Ringdén
authors.affiliation: Cancer Care Manitoba, University of Manitoba, Winnipeg, MB, Canada;
authors.forename: Marlis L
authors.initials: ML
authors.lastname: Schroeder
authors.affiliation: Center for International Blood and Marrow Transplant Research, Minneapolis, MN;
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Spellman
authors.affiliation: National Reference Laboratory for Histocompatibility, Department of Genetics and Laboratory Medicine, University Hospital Geneva, Geneva, Switzerland;
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Tiercy
authors.affiliation: European Group for Blood and Marrow Transplantation and University of Perugia, Perugia, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Velardi
authors.affiliation: Department of Clinical Immunology, Royal Perth Hospital, Perth, Australia;
authors.forename: Campbell S
authors.initials: CS
authors.lastname: Witt
authors.affiliation: Cancer and Inflammation Program, SAIC Frederick, Inc., Frederick National Laboratories for Cancer Research, Frederick, MD; and.
authors.forename: Colm
authors.initials: C
authors.lastname: O'Huigin
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Apps
authors.affiliation: 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.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D005260:Female; D006086:Graft vs Host Disease; D015236:HLA-C Antigens / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation; D006648:Histocompatibility / Q000276:immunology; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009190:Myelodysplastic Syndromes / Q000276:immunology / Q000628:therapy*; D012189:Retrospective Studies; D016896:Treatment Outcome; D061349:Unrelated Donors; D055815:Young Adult
chemical_list: D015236:HLA-C Antigens