Molecular Immunology 45 (2008) 3631–3638 Contents lists available at ScienceDirect Molecular Immunology journal homepage: www.elsevier.com/locate/molimm KIR2DS5 is associated with leukemia free survival after HLA identical stem cell transplantation in chronic myeloid leukemia patients Arnold van der Meer a,∗ , Nicolaas P.M. Schaap b , Anton V.M.B. Schattenberg b , Bram van Cranenbroek a , Henk J. Tijssen a , Irma Joosten a a Department of Blood Transfusion and Transplantation Immunology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands b Department of Hematology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands article info Article history: Received 21 April 2008 Accepted 24 April 2008 Available online 16 June 2008 Keywords: Stem cell transplantation Chronic myeloid leukemia Killer cell immunoglobulin-like receptor Natural killer cell HLA identical sibling abstract Background: Alloreactive NK cells play a role in tumor eradication after allogeneic HLA mismatched stem cell transplantation (SCT). The effect of NK alloreactivity in HLA identical SCT is still under debate and in particular in transplantation for chronic myeloid leukemia (CML) the data are very limited and with conflicting outcome. The aim of our study was to evaluate the effect of KIR genes and KIR ligands on leukemia free survival (LFS) and relapse rate in a well-defined, homogeneous group of CML patients phase upon HLA identical sibling SCT. Methodology: We retrospectively analyzed the effect of KIRs and KIR ligands (C1 and C2) on LFS and relapse in 70 CML patients in 1st chronic phase, who had received an HLA identical sibling graft. For KIR typing we used a single PCR based KIR typing protocol that also included primers allowing for the identification of the KIR binding site on HLA-Cw (AA 77 and 80). Principal findings: The data show clear differences in transplant outcome between patients having both ligands (C1 and C2) as compared to patients having only one ligand (C1 or C2). In the latter group, the stimulatory KIR2DS5 gene was associated with improved leukemia free survival (p = 0.007; hazard ratio 4.3; 95% confidence interval 1.3–6.7) and lower relapse rates (p = 0.028; HR 4.3, 95% CI 1.1–9.1). In contrast, in patients carrying both ligands, KIR2DS5 was associated with reduced LFS (p = 0.0056; HR 0.3; 95% CI 0.1–0.7) and higher relapse rate (p = 0.02; HR 0.35, 95% CI 0.1–0.8). Conclusions: Our data indicate a role for an NK mediated anti-CML response after HLA identical sibling SCT that is influenced by KIR ligands and, more importantly, by stimulatory KIRs present in the donor. © 2008 Elsevier Ltd. All rights reserved. 1. Introduction Allogeneic stem cell transplantation (SCT) is an effective immune therapy for hematological malignancies. In particular for chronic myeloid leukemia (CML), allogeneic SCT is the only cura- tive treatment to date. The success of allogeneic SCT at least partly depends on the anti-tumor response mounted by donor lympho- cytes. NK cells have been identified as important mediators of an anti-leukemic response after HLA mismatched haploidentical or unrelated stem cell transplantation (Giebel et al., 2003; Leung et al., 2004; Ruggeri et al., 2002; Elmaagacli et al., 2005). This could be ascribed to HLA class I mismatches, affecting the availability of epi- topes necessary for NK cell recognition. The absence of an inhibitory ligand for NK cell receptors was associated with an anti-tumor response after SCT for acute myeloid leukemia (AML) (Ruggeri et ∗ Corresponding author. Fax: +31 24 36 19415. E-mail address: a.vandermeer@abti.umcn.nl (A. van der Meer). al., 2002; Giebel et al., 2003; Leung et al., 2004), CML (Ruggeri et al., 1999; Giebel et al., 2003; Elmaagacli et al., 2005), myelodys- plastic syndrome (MDS) (Giebel et al., 2003) and childhood ALL (Leung et al., 2004), resulting in a reduction of the relapse rate and prolonged (disease free) survival of the patients. This concept was further supported by the presence of alloreactive donor NK cells in patients after transplantation (Ruggeri et al., 1999), coinciding with a reduced risk of relapse. These cells could only be detected during the first few months after transplantation, suggesting that there is a window of opportunity for alloreactivity during the period that the donor NK repertoire is rebuilding in the patient. NK cells are part of the innate immune response. They contribute to the immediate response to virally infected cells and tumor cells. Next to direct killing of target cells, NK cells can also play a role in tuning and activating the adaptive immune response by inter- acting with dendritic cells and T-cells (Moretta, 2002). Activation of NK cells is in part modulated by stimulatory and inhibitory receptors that can bind to HLA class I molecules, the killer cell immunoglobulin like receptors (KIRs). KIRs are a family of approx- 0161-5890/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.molimm.2008.04.016