Allogeneic MHC‐mismatched activated natural killer cells administered after bone marrow transplantation provide a strong graft‐versus‐leukaemia effect in mice

Abstract

Summary. Allogeneic lymphocytes administered with an unmanipulated bone marrow transplant provide a strong antileukaemic effect, the so-called graft-versus-leukaemia (GVL) effect. On the other hand, T-cell-mediated graftversus-host-disease (GVHD) observed after transplantation of unmanipulated BM graft causes substantial morbidity and mortality. The aim of the present study was to determine the antileukaemic potential of enriched IL-2 activated NK cells administered 2 h after BMT. Balb/c (H-2 d ) mice were given a dose of A20 (H-2 d , B-cell leukaemia) cells 2 d prior to lethal total body irradiation (TBI) and transplantation of either syngeneic or allogeneic anti-Thy1.2 (CD90) depleted bone marrow cells. Either syngeneic (Balb/c, H-2 d ) or allogeneic (C57BL/6, H-2 b ) enriched and IL-2 (200 U/ml for 24 h) activated NK cells were given 2 h after BMT. Injection of A20 leukaemia into normal Balb/c recipients led to death after a median of 14 d. A lethal dose of TBI followed by either syngeneic or allogeneic Thy1.2-depleted BMT resulted in a modest antileukaemic effect. The adoptive transfer of syngeneic enriched and IL-2 preincubated NK cells given at time of BMT exerted a significantly better GVL effect. However, the infusion of allogeneic enriched NK cells resulted in a stronger GVL effect. These results clearly demonstrate that allogeneic NK cells are superior to syngeneic NK cells in their potential to eradicate residual leukaemia cells after BMT without mediating clinical overt GVHD. This experimental setting may offer a strategy for treatment of haematological malignancies in a phase of minimal residual disease.

Allogeneic cell-mediated immunotherapy of leukemia with immune donor lymphocytes to upregulate antitumor effects and downregulate antihost responses

“…Alternatively, GVL and GVHD could be mediated by different T-cell clones 19 including NK cells that may react against tumor cells but not against normal cells. 20 Lymphocyte activation may also result in IL-2-dependent activation of NK cells 15,21 or alloreactive NK cells. 24 Another possible explanation is that tumor cells are more sensitive to allogeneic effector T cells than normal target cells or that the tumor cells fail to induce apoptosis of alloreactive T cells, whereas normal allogeneic cells theoretically may have this capacity.…”

Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect

“…Infusion of allogeneic NK cells (presumably containing NK cells not recognizing recipient MHC) has not been associated with the development, but sometime associated with suppression, of GVHD. [128][129][130] The Perugia study 125 directly addressed this point by infusing high numbers of purified host-reactive NK cells into lethally irradiated mice. 125 No GVHD whatsoever was observed.…”

Analysis of donor NK and T cells infused in patients undergoing MHC-matched allogeneic hematopoietic transplantation

“…Indeed, IL-2-activated NK cells infused in syngeneic mouse exert a significant GVL effect. 28 Moreover, it has recently been demonstrated, in vivo in the mouse, that NK cells can reject tumor cell lines expressing syngeneic MHC class I molecules. 29,30 In this study, we analyzed the NK cell and T cell compartments present in hematopoietic bone marrow grafts and aphereses which were infused in adult patients undergoing MHCmatched and non-T cell-depleted allogeneic transplantation.…”