Effect of missing killer-immunoglobulin-like receptor ligand in recipients undergoing HLA full matched, non-T-depleted sibling donor transplantation: a single institution experience of 151 Asian patients

Abstract

This retrospective analysis studied the impact of natural killer (NK) alloreactivity based on the missing ligand model, for a cohort of recipients undergoing haemopoietic stem cell transplant without T-cell depletion from HLA full-matched sibling donors. All patients received a uniform myeloablative conditioning regimen and prophylaxis for GVHD. A total of 151 patients were studied, including 62 patients with AML or myelodysplastic syndrome, 42 patients with ALL and 47 patients with CML. We found that 81% of patients had at least one missing KIR-ligand (KIR-L), and HLA-C1 allogroup homozygosity is present in 70% of patients. From multivariate analysis, we observed that the only consistently significant factor that was associated with superior survival was disease stage. Missing KIR-L, whether considering HLA-Bw and HLA-C alleles, without or with HLA-A ligands or narrowing to only HLA-C alleles alone to classify the number of missing KIR-L, did not have any impact on OS or relapse-free survival. This negative finding implies that as the KIR-L composition of recipient is not important in this matched non-T-depleted setting, further immunotherapeutic measures involving adoptive NK cell infusions have to be explored to exploit the benefit of NK alloreactivity for such transplants.

Bone marrow may be the preferable graft source in recipients homozygous for HLA-C group 2 ligands for inhibitory killer Ig-like receptors

“…In fact, those studies favoring the missing KIR ligand model were largely based on BMT and/or T cell-depleted HSCT. 3,5,[16][17][18]25 On the contrary, most of the studies questioning the missing KIR ligand model were based on combined analyses of BMT and PBSCT, 12,14,20 or were restricted to PBSCT. 21 As an exception, Gagne et al, 22 have reported poor outcome in C2/2 recipients with myelogenous diseases following BMT.…”

“…19 Furthermore, a number of clinical studies aimed at reproducing the model have yielded seemingly conflicting results. 3,5,[12][13][14][15][16][17][18][19][20][21]25 So far, the missing KIR ligand model has therefore been considered at best to be of predictive value without suggesting practical consequence, as it relies on the recipient's HLA type, which is evidently irrevocable. Contrasting with this consideration, the present study suggests that a significant advantage might be taken from the differential effects of missing KIR ligands in BMT vs PBSCT.…”

“…Several studies were compatible with the missing KIR ligand model. 3,5,[15][16][17][18] However, others did not reveal a benefit of missing KIR ligands, 13,19,20 or even showed an adverse effect, particularly in C2/2 recipients. 12,14,21,22 In T cell replete, non-antithymocyte globulin (ATG)-based sibling PBSCT, we have recently reported a superior OS and PFS in C1/2 heterozygous recipients compared with C2/2 recipients, 21 a finding diametrically opposed to the missing KIR ligand model.…”

Killer immunoglobulin-like receptor (KIR) and KIR–ligand genotype do not correlate with clinical outcome of renal cell carcinoma patients receiving high-dose IL2

“…Since KIR and HLA are inherited independently on chromosome 19 and chromosome 6, respectively [8], an individual may lack one or more HLA epitopes for their inhibitory KIR genes; such individuals are referred to as having a “KIR-ligand missing” genotype. This KIR/KIR-ligand genotype is present in more than 60% of the population [18,6]. Alternatively, those individuals that have HLA epitopes for all of their inherited inhibitory KIR genes are referred to as having “all KIR-ligands present”.…”

The effect of missing KIR ligands, activating KIR genotype and haplotype on the outcome of T‐cell‐replete hematopoietic stem cell transplantation from HLA‐identical siblings in Thai patients

“…Despite a number of supportive studies for the role of KIR genotypes in HSCT, there are contradicting studies that report negative or controversial association (6,(18)(19)(20)(21). Particularly, there are only a few studies with limited sample size on the effect of KIR genotype in HLA-identical sibling HSCT in Asian population of which use non-T depleted protocols (12,17,20,(22)(23)(24). As the KIR-HLA class I relationship between recipient and donor might become an additional part of the donor evaluation and selection process, more samples and data analysis should be included to reach the conclusion of the usefulness of this additional promising KIR genotyping.…”