CD3+/CD19+-depleted grafts in HLA-matched allogeneic peripheral blood stem cell transplantation lead to early NK cell cytolytic responses and reduced inhibitory activity of NKG2A

Abstract

Natural killer (NK) cells have an important function in the antitumor response early after stem cell transplantation (SCT). As part of a prospective randomized phase III study, directly comparing the use of CD3 þ /CD19 þ -depleted peripheral blood stem cell (PBSC) harvests with CD34 þ -selected PBSC harvests in allogeneic human leukocyte antigen-matched SCT, we here show that the use of CD3 þ /CD19 þ -depleted PBSC grafts leads to early NK cell repopulation and reconstitution of the CD56 dim and CD56 bright NK cell subsets, with concomitant high cytolytic capacity. In the CD34 group, this process took significantly longer. Moreover, in the CD3/19 group after reconstitution, a higher percentage of killer immunoglobulin-like receptor-positive NK cells was found. Although similar percentages of CD94-positive NK cells were found in both groups, in the CD34 group, almost all expressed the inhibitory CD94:NKG2A complex, whereas in the CD3/19 group, the inhibitory CD94:NKG2A and the activating CD94:NKG2C complex were equally distributed. This preferential development of NKG2C-expressing NK cells in the CD3/19 group was paralleled by a loss of NKG2A-mediated inhibition of NK cell degranulation. These results show that the use of CD3 þ /CD19 þ -depleted grafts facilitates strong NK cell cytolytic responses directly after SCT, and the rapid emergence of an NK cell receptor phenotype that is more prone to activation.

Defining Early Human NK Cell Developmental Stages in Primary and Secondary Lymphoid Tissues

“…These data confirmed previous research describing the abundant presence of CD56 bright NK cells in SLT [11,12]. In addition, we and others have shown that CD56 bright cells are the first mature NK cells to arise after allogeneic stem cell transplantation (SCT) [13,14]. Overall, these data support a model of in vivo human NK cell development in which CD34…”

Licensed to Kill: Towards Natural Killer Cell Immunotherapy

“…Previously, Gentilini et al even showed a significant faster and sustained recovery of NK cells in a group of patients after RIC allogeneic SCT with CD3 + /CD19 + depleted grafts in comparison with patients with myeloablative allogeneic SCT with CD34 + selected grafts combined with adoptive NK cell infusion two days post SCT (Gentilini et al, 2007). Overall, these studies suggest that the use of NK cell rich grafts is favourable for the facilitation of fast and sustained NK cell recovery and differential reconstitution of the NK cell receptor repertoire, which may lead to improved donor NK cell alloreactivity in the GVL direction (Eissens et al, 2010a). Further prospective comparisons of the different graft manipulation methods for allogeneic SCT in the HLA-matched or haploidentical setting are warranted for more detailed analysis of the impact of graft composition on immune reconstitution.…”

“…The use of enriched NK cell grafts for allogeneic SCT has shown to be beneficial for transplant outcome and provides enhanced GVL reactivity directly after transplantation as compared with conventional grafts that lack NK cells (Bethge et al, 2006;Eissens et al, 2010a;Kim et al, 2006). In addition, the head start in GVL reactivity may lead to better outcomes in terms of infectious events and overall survival after allogeneic SCT (Kim et al, 2005a).…”

“…In these cases, optimal functional activity of NK cells already in the early phase after SCT is essential, and therefore the presence of NK cells in the graft appears to be beneficial for transplant outcome (Bethge et al, 2006;Kim et al, 2005a). As part of a prospective randomized phase III study, we directly compared the alloreactive potential of allogeneic donor NK cells between patients having either received a CD3 + /CD19 + cell depleted graft (containing substantial NK cell numbers) or a conventional CD34 + selected graft (devoid of NK cells) in the setting of HLA-matched SCT (Eissens et al, 2010a). Results demonstrate that patients having received a CD3 + /CD19 + cell depleted graft, exhibited a faster recovery of NK cells and a functional NK cell receptor repertoire of inhibitory and stimulatory receptors as compared with patients having received a conventional CD34 + graft.…”

Donor Natural Killer Cells and Their Therapeutic Potential in Allogeneic Hematopoietic Stem Cell Transplantation

“…These results indicated that the early reconstituting NK cells after HSCT were mainly generated from the differentiation and maturation of NK precursors but not the expansion of mature NK cells in the graft. Nevertheless, the expansion of adoptive transferred NK cells also influences the reconstitution of donor NK cells since Eissens et al find that in HLA-matched allogeneic peripheral blood stem cell transplantation, CD3 + /CD19 + -depleted grafts which contain more mature NK cells than CD34 + -selected grafts lead to more rapid NK cell reconstitution [93]. + phenotype for at least 3-6 months [94].…”