Determinants of Antileukemia Effects of Allogeneic NK Cells

Abstract

In HLA-nonidentical bone marrow transplantation, we studied the characteristics of donor NK cells, recipient leukemia cells, and the cytokine environment that predict the antileukemia effects of allogeneic NK cells. We found that the risk of relapse in pediatric patients with hematologic malignancies was best predicted by a model taking into consideration the presence of inhibitory killer cell Ig-like receptors (KIRs) on the donor’s NK cells and the absence of corresponding KIR ligand in the recipient’s HLA repertoire (a receptor-ligand model). The risk of relapse was prognosticated less precisely by the Perugia donor-recipient KIR ligand-ligand mismatch model or by a natural cytotoxicity model. In contrast to the ligand-ligand model, we found that the new receptor-ligand model was accurate when analysis was applied to patients with lymphoid malignancy. These findings corroborate our observations that the recipient’s KIR repertoire, which was derived from highly purified, HLA-disparate CD34+ cells, resumed a donor-specific pattern within 3 mo of transplantation, but did not correlate evidently with the donor or recipient ligand repertoire. In an in vitro assay and an in vivo mouse model, human NK cell cytotoxicity toward human leukemia cells with 11q23 chromosomal rearrangement increased with the number of receptor-ligand mismatch pairs or prestimulation with IL-12 and IL-18. These findings provide new insights into the determinants of antileukemia effects of allogeneic NK cells and therapeutic strategies.

Relevance of C1 and C2 Epitopes for Hemopoietic Stem Cell Transplantation: Role for Sequential Acquisition of HLA-C-Specific Inhibitory Killer Ig-Like Receptor

“…Whereas a beneficial influence of KIR ligand mismatching on leukemic relapse as well as survival was observed in some studies (8,9), similar effects were not seen in others (10,11). Recently, a combined analysis of KIR ligands together with DNAor RNA-based KIR typing was suggested as better predictors of clinical outcome (12,13).…”

Cytolytic activity of NK cell clones against acute childhood precursor-B-cell leukaemia is influenced by HLA class I expression on blasts and the differential KIR phenotype of NK clones

“…Recently, in a limited number of paediatric patients with lymphatic leukaemia, a lower relapse rate after mismatched transplantation was attributed to NK cell alloreactivity: 21 NK cell alloreactivity correlated to KIR-ligand mismatch within the HLA-I alleles of donor and recipient. 10,22 In particular, three groups of KIRs and their ligands have been considered to play a predominant role in this model: Cw3-related HLA C alleles (recognized by CD158b), Cw4-related HLA C alleles (recognized by CD158a) and HLA Bw4 alleles (recognized by CD158e).…”

“…NK cells derived from those progenitors acquired a specific pattern of KIR expression step by step within the first 3 months. 21 During this period of receptor acquisition post-allogeneic SCT, subsets of NK cells could express none or only one KIR. 27 NK cells with inappropriate inhibitory receptors for self-HLA have been characterized in mice and man 28 as hyporesponsive and self-tolerant, 29,30 whereas activity of NK cells with appropriate KIR expression is determined by class and quantity of inhibitory receptors for self-HLA-B and HLA-C ligand.…”

The beneficial impact of missing KIR ligands and absence of donor KIR2DS3 gene on outcome following unrelated hematopoietic SCT for myeloid leukemia in the Chinese population

“…Another algorithm, termed the 'missing ligand' or 'receptor-ligand' model, has therefore been proposed for predicting clinical outcome. 14,31,32 Because most individuals have inhibitory KIRs for HLA-C1, C2 and Bw4, we explored a model based on recipient HLA typing alone to determine KIR ligand status. This is possibly the first such analysis for a Chinese patient population for unrelated donor stem cell transplants.…”