title: Hematopoietic stem cell transplantation: Improving alloreactive Bw4 donor selection by genotyping codon 86 of KIR3DL1/S1.
abstract: KIR3DL1 is a natural killer (NK) cell receptor that recognizes the Bw4 epitope of human leukocyte antigen (HLA) class I molecules. Following hematopoietic stem cell transplantation for patients lacking Bw4, KIR3DL1-expressing NK cells from Bw4-positive donors can be alloreactive and eliminate tumor cells. However, KIR3DL1 alleles having T instead of C at nucleotide 320 (encoding leucine 86 instead of serine 86) are not expressed on the cell surface. Thus, not all individuals testing positive for KIR3DL1 are optimal donors for Bw4-negative recipients. Therefore, we developed a method for genotyping codon 86, which was validated by its perfect correlation with NK cell phenotype for 100 donors of diverse KIR3DL1/S1 genotype. We typed 600 donors and found that ∼12.2% had the KIR3DL1 gene, but did not express cell-surface KIR3DL1. By contrast, high-expressing allotypes were identified when haplotypes from four families with duplicated KIR3DL1/S1 genes were characterized at high resolution. Identifying donors who have KIR3DL1 but lack cell-surface KIR3DL1 would refine donor selection. With this technique, the number of individuals identified who may not be optimal donors for Bw4-negative patients increases by threefold, when compared with standard methods. Taken together, we propose that allele typing of killer cell Ig-like receptor (KIR) polymorphisms should become a standard practice when selecting donors.
authors.affiliation: Dipartimento di Medicina Sperimentale, University of Genoa, Genoa, Italy.|Centro di Eccellenza per la Ricerca Biomedica, University of Genoa, Genoa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Alicata
authors.affiliation: IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pende
authors.affiliation: IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Meazza
authors.affiliation: Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Canevali
authors.affiliation: Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Loiacono
authors.affiliation: Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bertaina
authors.affiliation: Bambino Gesù Children's Hospital, Rome, Italy.|Department of Pediatrics, University of Pavia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Neda
authors.initials: N
authors.lastname: Nemat-Gorgani
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Guethlein
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
authors.affiliation: Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.affiliation: Dipartimento di Medicina Sperimentale, University of Genoa, Genoa, Italy.|Centro di Eccellenza per la Ricerca Biomedica, University of Genoa, Genoa, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
authors.affiliation: Dipartimento di Medicina Sperimentale, University of Genoa, Genoa, Italy.|Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bottino
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Norman
authors.affiliation: Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Falco
mesh_terms: D000483:Alleles; D002462:Cell Membrane / Q000378:metabolism; D003062:Codon; D046148:Donor Selection; D015870:Gene Expression; D005838:Genotype; D015235:HLA-B Antigens / Q000276:immunology*; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D054341:Receptors, KIR3DL1 / Q000235:genetics* / Q000378:metabolism; D054349:Receptors, KIR3DS1 / Q000235:genetics* / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D003062:Codon; D015235:HLA-B Antigens; C042388:HLA-Bw4 antigen; C515083:KIR3DL1 protein, human; D054341:Receptors, KIR3DL1; D054349:Receptors, KIR3DS1
keywords: Donor selection; HLA haploidentical hematopoietic stem cell transplantation; Killer cell Ig-like receptor (KIR); Natural killer (NK) cell; Next-generation sequencing