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

  title={NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect.},
  author={Stephanie Nguyen and Nathalie Dh{\'e}din and Jean Paul Vernant and Mathieu Kuentz and Ahmad Al Jijakli and Nathalie Rouas-Freiss and Edgardo Delfino Carosella and Ali Boudifa and Patrice Debré and Vincent Vieillard},
  volume={105 10},
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… 

Figures and Tables from this paper

Involvement of mature donor T cells in the NK cell reconstitution after haploidentical hematopoietic stem-cell transplantation

Despite the strong graft-versus-host disease (GvHD) reaction, pTCD patients, with T cells present during SCT, had a better clinical outcome than patients with eTCD transplants, and this finding strongly suggest that mature donor T cells in the graft may play a key role in NK cell differentiation in vivo, after haploidentical SCT.

The Activating NKG2C Receptor Is Significantly Reduced in NK Cells after Allogeneic Stem Cell Transplantation in Patients with Severe Graft-versus-Host Disease

Results show that NK cells expressing the activating CD94/NKG2C receptor are significantly reduced in patients after alloSCT with severe acute and chronic graft-versus-host disease (GvHD).

Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation.

A first-in-human trial of adoptive transfer of donor-derived IL-15/4-1BBL-activated NK cells (aNK-DLI) following HLA-matched, T-cell-depleted nonmyeloablative peripheral blood stem cell transplantation in children and young adults with ultra-high-risk solid tumors concludes that aNK- DLI contributed to the acute GVHD observed.

Reconstitution of multifunctional CD56lowCD16low natural killer cell subset in children with acute leukemia given α/β T cell-depleted HLA-haploidentical haematopoietic stem cell transplantation

It is suggested that NK cells reconstituted after HLA-haploidentical haematopoietic stem cell transplantation play an important role in host defense against leukemia relapse and infections after HSCT, and represent an ideal candidate for approaches of adoptive immunotherapy.

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

It is shown that the use of CD3+/CD19+-depleted PBSC 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.

Cellular and molecular basis of haploidentical hematopoietic stem cell transplantation in the successful treatment of high-risk leukemias: role of alloreactive NK cells

Novel approaches are in progress to further improve the clinical outcome based on the infusion of donor alloreactive NK cells either as a component of the transplanted cell population or as in vitro expanded NK cells.



Reconstitution of dendritic and natural killer-cell subsets after allogeneic stem cell transplantation: effects of endogenous flt3 ligand.

It is demonstrated that endogenous FL has distinct effects on the kinetics of reconstitution of DCs and NK cells and have potential implications for the modulation of immune responses after allogeneic SCT.

Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation.

A GVL effector and engraftment facilitating mechanism, which is independent of T-cell-mediated GVH reactions, may be operational in HLA mismatched hematopoietic cell transplants.

Analysis of the activating receptors and cytolytic function of human natural killer cells undergoing in vivo differentiation after allogeneic bone marrow transplantation

Analysis of NK cells at day 30 after bone marrow transplantation revealed the occurrence of both phenotypic and functional maturation, in agreement with a previous in vitro study showing that immature NK cell precursors express CD16, NKG2D and KIR only at a late stage of differentiation and also express inhibitory 2B4.

The beneficial role of inhibitory KIR genes of HLA class I NK epitopes in haploidentically mismatched stem cell allografts may be masked by residual donor-alloreactive T cells causing GVHD.

It is suggested that lack of extensive T-cell depletion in haploidentical transplantation is associated with high GVHD rates and diminishes the benefits of NK-cell alloreactivity.

Successful engraftment of T-cell-depleted haploidentical "three-loci" incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum.

Results show that a highly immunosuppressive and myeloablative conditioning followed by transplantation of a large number of stem cells depleted of T lymphocytes by soybean agglutination and E-rosetting technique has made transplation of three HLA-antigen disparate grafts possible, with only rare cases of GVHD.

Phenotypic and functional reconstitution of peripheral blood lymphocytes following T cell-depleted bone marrow transplantation from partially mismatched related donors

The need for long-term immunophenotypic monitoring as well as prolonged infection surveillance and prophylaxis is suggested for patients with leukemia and other disorders of hematopoiesis.

Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation.

It is demonstrated that a majority of HLA-matched hematopoietic cell transplantations involve KIR mismatch and differences in NK cell repertoire having potential impact for immune responsiveness and transplantation outcome are revealed.

CD16- CD56+ natural killer cells after bone marrow transplantation.

Two different NK cell subsets may reflect distinct activation or differentiation steps of NK cells during reconstitution of the immune system during follow-up after autologous or allogeneic bone marrow transplantation.

Orderly and Nonstochastic Acquisition of CD94/NKG2 Receptors by Developing NK Cells Derived from Embryonic Stem Cells In Vitro1

The acquisition of CD94/NKG2 by NK cells as they differentiate from ES cells in vitro is nonstochastic, orderly, and cumulative, and it is reported that the acquisition of these individual receptor gene expressions during different stages of differentiation fromES cells to NK cells follows a predetermined order.

Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor.

The data show no advantage for KIR ligand incompatibility in this clinical setting as assessed by HLA-Bw4 and Hla-C alleles, and it is possible that there will be a benefit of NK cell alloreactivity if strategies of haploidentical transplantation are used: high stem cell doses, extensive T-cell depletion, and no postgrafting immune suppression.