Activating killer‐cell immunoglobulin‐like receptor haplotype influences clinical outcome following HLA‐matched sibling haematopoietic stem cell transplantation

Abstract

Natural killer cells are thought to influence the outcome of hematopoietic stem cell transplant (HSCT), impacting on relapse, overall survival, graft versus host disease and the control of infection, in part through the complex interplay between the large and genetically diverse killer immunoglobulin-like receptor (KIR) family and their ligands. This study examined the relationship between KIR gene content and clinical outcomes including the control of opportunistic infections such as cytomegalovirus in the setting of human leucocyte antigen (HLA)-matched sibling HSCT in an Australian cohort. The presence of the KIR B haplotype which contain more activating receptors in the donor, in particular centromeric B haplotype genes (Cen-B), was associated with improved overall survival of patients with acute myeloid leukemia (AML) undergoing sibling HSCT and receiving myeloablative conditioning. Donor Cen-B haplotype was also associated with reduced acute graft versus host disease grades II-IV whereas donor telomeric-B haplotype was associated with decreased incidence of CMV reactivation. In contrast, we were not able to demonstrate a reduced rate of relapse when the donor had KIR Cen-B, however relapse with a donor Cen-A haplotype was a competing risk factor to poor overall survival. Here we show that the presence of donor activating KIR led to improved outcome for the patient, potentially through reduced relapse rates and decreased incidence of acute GvHD translating to improved overall survival. This article is protected by copyright. All rights reserved.

Influence of KIR and NK Cell Reconstitution in the Outcomes of Hematopoietic Stem Cell Transplantation

“…Cooley et al observed that patients with AML with KIR-B/x donors experienced a 30% improvement in RFS compared with those with A/A donors ( 40 ). Subsequently, many further investigations confirmed this beneficial effect of the KIR-B haplotype on relapse and survival in patients with hematological malignancies ( 50 , 51 , 57 , 67 , 72 , 76 , 79 , 81 , 85 , 88 – 92 , 96 , 98 , 101 – 104 ). Five of these studies reported that the protection effects mainly existed in the KIR Cen-B locus ( 67 , 88 , 91 , 92 , 96 ).…”

“…Regarding specific genotypes, some studies have reported that KIR haplotype B donors afforded a significantly reduced risk of GVHD ( 60 , 63 , 86 , 96 ). Consistent with these findings, Sivori et al suggested that donor NK cells expressing KIR2DS1 were efficient in killing allogenic dendric cells in the setting of haplo-HSCT, thus leading to a better GVHD control ( 136 ).…”

“…Many studies have found that KIR-B genes protect patients with HSCT against infections and most of them were predominantly T cell replete (TCR) transplants ( 81 , 84 , 87 , 96 , 139 , 140 ). Cook et al first observed that KIR haplotype B donors exhibited a significant reduction in the rate of CMV reactivation in sibling allo-HSCT ( 139 ).…”

“…Specifically, activating KIR2DS2 and KIR2DS4 may play a major protective role ( 84 , 140 ). Importantly, transplantations from donors with KIR2DS1 correlated with better infectious control ( 51 , 96 ). Mancusi et al further demonstrated that the binding of KIR2DS1 to HLA-C2 triggered pro-inflammatory cytokine production by alloreactive NK cells ( 51 ).…”

“…Babor et al further suggested that the presence of Cen-B with absence of Tel-B improved leukemia control in pediatric patients with ALL ( 97 ). At the genetic level, the KIR2DS2 gene, which is located on the Cen-B motif ( 72 , 76 , 79 , 90 , 92 , 96 ), and the KIR2DS1 gene, located on the Tel-B motif ( 51 , 72 , 82 , 98 ), were found to be related to a decreased relapse rate or an improved survival. However, several studies found that Cen-B donors indicated a lower OS ( 56 , 70 , 100 ).…”