Hematopoietic stem cell transplantation: Improving alloreactive Bw4 donor selection by genotyping codon 86 of KIR3DL1/S1 |
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Authors: | Claudia Alicata Daniela Pende Raffaella Meazza Paolo Canevali Fabrizio Loiacono Alice Bertaina Franco Locatelli Neda Nemat‐Gorgani Lisbeth A. Guethlein Peter Parham Lorenzo Moretta Alessandro Moretta Cristina Bottino Paul J. Norman Michela Falco |
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Affiliation: | 1. Dipartimento di Medicina Sperimentale, University of Genoa, Genoa, Italy;2. Centro di Eccellenza per la Ricerca Biomedica, University of Genoa, Genoa, Italy;3. IRCCS AOU San Martino‐IST, Genoa, Italy;4. Istituto Giannina Gaslini, Genoa, Italy;5. Bambino Gesù Children's Hospital, Rome, Italy;6. Department of Pediatrics, University of Pavia, Italy;7. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA;8. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA |
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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. |
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Keywords: | Donor selection HLA haploidentical hematopoietic stem cell transplantation Killer cell Ig‐like receptor (KIR) Natural killer (NK) cell Next‐generation sequencing |
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