Donor KIR Genotype Research Articles

Donor Activating Kir Genes and Survival after Haplo-Identical Hematopoietic Transplantation.

Although NK cell alloreactivity impacts beneficially on the outcome of haploidentical transplantation in AML patients, largely through its GvL effect (Ruggeri et al, Science 2002), TRM (~40%, largely due to infections) remains a major problem. In a search for additional donor selection criteria, here we determined the donor KIR genotypes and correlated them with transplantation outcomes in 74 AML recipients. Transplants from donors carrying group A KIR haplotype genes, which mainly encode for inhibitory receptors (and for the activating KIR2DS4 gene) (n=22), were compared with those from donors carrying group B KIR haplotype genes, which encode for additional activating KIRs (KIR2DS1, 2, 3, 5 and KIR3DS1) (n=52). Event-free survival appeared better in AML patients transplanted from donors bearing B haplotype genes (48% vs 23%, p=0.066). As expected, other well established factors of good prognosis, such as NK cell alloreactivity and disease status at transplant, played significant independent roles (H.R.=0.42 donor NK cell alloreactivity present vs absent, 95% C.I.=0.22–0.79, p=0.007; H.R.=0.39 remission vs relapse at transplant, 95% C.I.=0.21–0.72, p=0.003). However, after adjusting for donor-vs-recipient NK cell alloreactivity and transplantation in remission, transplantation from donors carrying group B haplotype KIR genes still tended to emerged as an independent predictor of survival (H.R.=0.56 B haplotype genes present vs absent, 95% C.I.=0.3–1.0, p=0.07). This might have been the consequence of reduced incidence of leukaemia relapse. In an analysis of factors involved in relapse, donor-vs-recipient NK alloreactivity and disease status at transplant were confirmed as strong independent protective factors (H.R.=0.18 donor NK cell alloreactivity present vs absent, 95% C.I.=0.05–0.68, p=0.01; H.R.=0.15 remission vs relapse at transplant, 95% C.I.=0.04–0.58, p=0.006). Transplantation from donors carrying activating group B haplotype KIR genes had no effect on relapse (H.R.=0.59 B haplotype genes present vs absent, 95% C.I.= 0.17–2.05, p>0.1). Strikingly, in analyzing TRM, transplantation from these donors was associated with a markedly reduced TRM (59% vs 30%, p=0.03), and emerged as the only statistically significant protective factor (H.R.=0.46 B haplotype genes present vs absent, 95% C.I.= 0.22–0.97, p=0.04), even when compared with NK cell alloreactivity (H.R.=0.56 donor NK cell alloreactivity present vs absent, 95% C.I.=.026–1.20, p>0.1) and disease status at transplant (H.R.=0.53 remission vs relapse at transplant, 95% C.I.=0.25–1.11, p=0.09). Thus, transplantation from donors carrying activating (group B haplotype) genes could be a new donor selection criterion which might help reduce infectious mortality after haploidentical hematopoietic transplantation.The mechanisms underlying this apparently improved immune competence remain to be investigated.

The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell transplantation for myeloid leukemia

AbstractKiller immunoglobulin–like receptors (KIRs) regulate cell activity of natural killer (NK) cells and some T cells. The predominant ligand for inhibitory KIRs is HLA-C, which subdivides into 2 groups based on the specificity of inhibitory KIRs. The ligands for activatory KIRs are unknown. Following hematopoietic stem cell transplantation (HSCT), recipient tissues may not express a ligand for KIRs present within the graft, and the combination of donor KIR and recipient HLA-C types could influence outcome. HLA and KIR genotypes were determined in 220 donor-recipient pairs from HLA-matched sibling HSCTs performed for myeloid (n = 112) and lymphoid (n = 108) diseases. In HSCTs performed for myeloid disease, overall survival was worse in patients homozygous for group 2 HLA-C (C2) than in patients who carried a group 1 HLA-C (C1) allele (P < .005). Moreover, this effect is seen only when the donor additionally carries the activating KIR gene KIR2DS2 (P = .045). No effect was seen in patients with lymphoid disease. Thus, in HLA-matched sibling HSCT for myeloid leukemia, patients homozygous for C2 alleles receiving a graft from a donor carrying the KIR gene KIR2DS2 have a significantly reduced chance of survival.