KIR genes and KIR ligands affect occurrence of acute GVHD after unrelated, 12/12 HLA matched, hematopoietic stem cell transplantation

Abstract

Interactions of polymorphic killer Ig-like receptor (KIR) receptors with KIR ligands have been shown to modify the outcome of hematopoietic SCT (HSCT). The association of these genetic factors with different transplantation endpoints, however, varies substantially, depending on clinical and study setup variables. We aimed to assess whether KIR ligands, KIR genes and KIR haplotypes are associated with HSCT outcome of 124 patients with various hematological malignancies, transplanted with 12/12 HLA matched grafts from unrelated donors. For this purpose, patient and donor KIR gene and KIR ligand polymorphisms were determined and correlated with clinical data in simple and multiple models. We found that a missing HLA-C2 ligand for donor inhibitory KIR2DL1 was significantly associated with an increased risk of acute GVHD (aGVHD) (II-IV) (hazard ratio (HR) = 2.23, 95% confidence interval (95% CI): 1.21-4.10, P = 0.010), as were the AA KIR haplotypes in patients and donors in HLA-C1CX (HR 2.37, 95% CI: 1.16-4.84, P = 0.018) and in HLA-Bw4 (HR = 3.20, 95% CI: 1.35-7.60, P = 0.008) patients. On the contrary, transplantation of HLA-C1C2 patients with KIR2DS2 positive grafts were associated with a decreased risk of aGVHD (II-IV) (HR 0.24, 95% CI: 0.07-0.85, P = 0.027). Thus, our single center study provides evidence for the modification of aGVHD risk by KIRs and their ligands. Bone Marrow Transplantation (2009) 44, 97-103; doi: 10.1038/bmt.2008.432; published online 26 January 2009