Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: Evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity

Daniela Pende, Stefania Marcenaro, Michela Falco, Stefania Martini, Maria Ester Bernardo, Daniela Montagna, Elisa Romeo, Celine Cognet, Miryam Martinetti, Rita Maccario, Maria Cristina Mingari, Eric Vivier, Lorenzo Moretta, Franco Locatelli, Alessandro Moretta

Research output: Contribution to journalArticlepeer-review

Abstract

We analyzed 21 children with leukemia receiving haploidentical hematopoietic stem cell transplantation(haplo-HSCT) from killer immunoglobulin(Ig)-like receptors(KIR) ligand-mismatched donors. We showed that, in most transplantation patients, variable proportions of donor-derived alloreactive natural killer(NK) cells displaying anti-leukemia activity were generated and maintained even late after transplantation. This was assessed through analysis of donor KIR genotype, as well as through phenotypic and func-tional analyses of NK cells, both at the polyclonal and clonal level. Donor-derived KIR2DL1+ NK cells isolated from the recipient displayed the expected capability of selectively killing C1/C1 target cells, including patient leukemia blasts.Differently, KIR2DL2/3+ NK cells displayed poor alloreactivity against leukemia cells carrying human leukocyte antigen(HLA) alleles belonging to C2 group. Unexpectedly, this was due to recognition of C2 by KIR2DL2/3, as revealed by receptor blocking experiments and by binding assays of soluble KIR to HLA-C transfectants. Remarkably, however,C2/C2 leukemia blasts were killed by KIR2DL2/3+(or by NKG2A+) NK cells that coexpressed KIR2DS1. This could be explained by the ability of KIR2DS1 to directly recognize C2 on leukemia cells.A role of the KIR2DS2 activating receptor in leukemia cell lysis could not be demonstrated. Altogether, these results may have important clinical implications for the selection of optimal donors for haplo-HSCT.

Original languageEnglish
Pages (from-to)3119-3129
Number of pages11
JournalBlood
Volume113
Issue number13
DOIs
Publication statusPublished - Mar 26 2009

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Immunology
  • Hematology

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