NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect

Abstract

Natural killer (NK) cell alloreactivity is reported to mediate strong GvL (graft versus leukemia) effect in patients after haploidentical stem-cell transplantation (SCT) for acute myeloid leukemia (AML). Because subsequent immune reconstitution remains a major concern, we studied NK-cell recovery in 10 patients with AML who received haplomismatched SC transplants, among whom no GvL effect was observed, despite the mismatched immunoglobulin-like receptor (KIR) ligand in the GvH direction for 8 of 10 patients. NK cells generated after SCT exhibited an immature phenotype: the cytotoxic CD3 ؊ CD56 dim subset was small, expression of KIRs and NKp30 was reduced, while CD94/NKG2A expression was increased. This phenotype was associated to in vitro lower levels of cytotoxicity against a K562 cell line and against primary mismatched AML blasts than donor samples. This impaired lysis was correlated with CD94/NKG2A expression in NK cells. Blockading CD94/NKG2A restored lysis against the AML blasts, which all expressed HLA-E, the ligand for CD94/ NKG2A. Our present study allows a better understanding of the NK-cell differentiation after SCT. These results revealed that the NK cells generated after haplomismatched SCT are blocked at an immature state characterized by specific phenotypic features and impaired functioning, having potential impact for immune responsiveness and transplantation outcome. (Blood. 2005;105:4135-4142)

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

“…This observation was true for samples with group A as well as group B haplotypes (data not shown). These data, together with previous observations of clinical NK cell reconstitution (20,21), suggest a model of sequential order of KIR expression for the HLA-C-specific inhibitory KIR that might be genetically predetermined (Fig. 4).…”

Natural killer cell immune escape in acute myeloid leukemia

“…39 Another NK cell escape mechanism demonstrated in the HSCT setting is the overexpression of the inhibitory receptor CD94/ NKG2A on reconstituted NK cells that recognizes human leukocyte antigen-E on AML blasts, which is associated with a low cytotoxic capacity. 40,41 AML cells themselves contribute to impaired NK cell-mediated killing by decreased or absent expression of surface ligands for various NK cell activating receptors, including NCRs and NKG2D. 27,28,42,43 Furthermore, AML cells can shed ligands for NKG2D, as demonstrated by the increased serum levels of MHC class I chain-related genes A and B (MICA/B) in AML patients compared with healthy controls.…”

“…[45][46][47] NK CELL-DIRECTED THERAPIES FOR AML The success of NK cell-directed immunotherapy involves the functionality of the reconstituted NK cell compartment of patients in complete remission post (standard) therapy. Several studies have demonstrated that the NK cell compartment recovers rapidly, but is accompanied with a skewing of cell subsets towards CD56 bright (that is, immature) NK cells (post HSCT 40,41,[74][75][76][77] or post consolidation chemotherapy 78 ), in some cases potently impairing the graft-versus-leukemia effect (for example, overexpression of the inhibitory receptor CD94/NKG2A was associated with impaired cytotoxicity 40,41 ). Therefore, it has been proposed that early modulation of NK cell immunity could improve therapy-related outcome.…”

Impact of the source of hematopoietic stem cell in unrelated transplants: Comparison between 10/10, 9/10‐HLAmatched donors and cord blood

“…In comparison with transplants from adult donors, UCB transplants offer the advantage of prompt availability for many recipients and a decreased risk of graft-versus-host disease (GVHD) [2,3], but such transplants are associated with a slower hematological and immune recovery, leading to a higher risk of infection [4,5]. Mismatched-unrelated donor transplants are associated in some studies with a lower risk of relapse, but a higher risk of GVHD [6,7], while haploidentical HSCT may be complicated by a high risk of relapse and delayed immune recovery [8][9][10].…”