IntroductionNatural killer (NK) cells have antigen-independent tumor cytotoxicity and have been shown in murine models to control and prevent tumor growth and dissemination. 1,2 However, the exact role that NK cells play in the control of cancer in humans remains a matter of controversy.NK cells do not rearrange genes coding for specific antigen receptors; rather, their recognition of targets is regulated through a balance of activating or inhibitory signals. 3 It is necessary to inactivate NK cells to prevent their destruction of normal host tissues. 4 Therefore, even in the presence of an activating ligand, inhibitory ligands expressed on cells may deliver overriding signals that culminate in a net suppression of NK cell function. Recently, a growing number of NK cell inhibitory and activating receptors were characterized. 5-8 NK cells can recognize major histocompatibility (MHC) class I and class I-like molecules through killer immunoglobulin-like receptors (KIRs) expressed on their surfaces. MHC class I ligation of KIRs on normal and malignant tissues suppresses NK cell function. MHC class I molecules fall into groups that serve as ligands for specific KIR, resulting in the inhibition of NK cell-mediated cytotoxicity. Polymorphisms in amino acids residing at positions 77 and 80 of HLA-C dictate specificity for its target KIR. 9-11 KIR2DL1 recognizes group 2 HLA-C molecules that have an asparagine at position 77 and a lysine at position 80, whereas KIR2DL2 and KIR2DL3 recognize group 1 HLA-C molecules that have a serine at position 77 and an asparagine at position 80.The inactivation of NK cells by self-HLA molecules might be a mechanism permitting malignant host cells to evade NK cellmediated immunity. Because tumor KIR ligands are always matched to NK cell KIR, autologous NK cells would be inhibited by MHC class I-expressing tumors, even in the presence of activating ligands. This may in part explain the failure of adoptively transfused autologous NK 12 or lymphokine-activated killer (LAK) cells to mediate antitumor effects against most metastatic solid tumors. 13 Only tumor cells that have lost MHC class I expression or have a dominant-activating ligand are predicted to be susceptible to such populations. 14 Ruggeri et al 15,16 and others 17 have shown allogeneic NK cells can mediate antileukemic effects against AML after allogeneic haploidentical and partially mismatched unrelated hematopoietic cell transplantation when KIR/KIR ligand incompatibility exists in the graft-versus-host (GVH) direction (defined as an MHC class I KIR ligand that is absent in the recipient but present in the donor). In this setting, donor NK cells expand that are not inhibited by For personal use only. on March 22, 2019. by guest www.bloodjournal.org From ligands expressed on recipient leukemia cells, substantially reducing the risk for disease relapse compared with those who receive KIR-compatible transplants. This beneficial effect does not appear to occur against acute lymphoblastic leukemia (ALL), perhaps because these popul...

Summary Allogeneic haematopoietic cell transplantation (HCT) can cure a variety of non‐malignant haematological disorders. Although transplant outcomes for selected patients with severe aplastic anaemia (SAA) and paroxysmal nocturnal haemoglobinuria (PNH) have improved, older age, allo‐immunisation from transfusions, prior immunosuppressive therapy and a prolonged time from diagnosis to transplantation are associated with worse outcome. Because of its potent immunosuppressive effects, we investigated a fludarabine‐based non‐myeloablative conditioning regimen in patients with transfusion‐dependent non‐malignant haematological disorders at increased risk for graft rejection with conventional transplant conditioning. Twenty‐six patients with transfusion dependent/anti‐thymocyte globulin (ATG)‐refractory SAA, PNH or pure red cell aplasia underwent HCT from a human leucocyte antigen (HLA)‐compatible relative. Transplant conditioning consisted of cyclophosphamide (120 mg/kg) and fludarabine (125 mg/m2) with or without ATG. Ciclosporine, alone or combined with mycophenolate mofetil or methotrexate, was used as graft‐versus‐host disease (GVHD) prophylaxis. All patients achieved durable engraftment and transfusion‐independence. Twenty‐four of 26 patients are alive at a median of 21 months following transplantation. Although a high cumulative incidence of acute (65% grades II–IV, 54% grades III–IV) and chronic GVHD (56%) was observed, only one patient died from transplant‐related causes (cumulative incidence 7%). These data show that HCT following fludarabine‐based non‐myeloablative conditioning results in durable engraftment and excellent survival in SAA and PNH patients at high risk for graft rejection.