The protective role of donor-derived KIR expression and HLA-Bw4 ligand recognition in reducing aGvHD after allogeneic transplantation

Aim: Killer-cell immunoglobulin-like receptors (KIRs) regulate natural killer (NK) cell alloreactivity through interactions with human leukocyte antigen (HLA) class I ligands.This process depends on the balance between activating KIRs (aKIRs) and inhibitory KIRs (iKIRs) , whereas the mechanism remains to be fully elucidated. Our study investigated the association of differential KIR expression levels with acute graft-versus-host disease (aGvHD) and explored the potential involvement of certain KIR/HLA ligand combinations in the aGvHD pathogenesis.

Methods: The study enrolled 236 patients with hematological malignancies. Blood was collected for DNA extraction; typing of the HLA loci was performed using sequence-based typing (SBT) ; typing of KIR genes was performed by sequence-specific oligonucleotide probe (SSOP).Total RNA samples were isolated and used for analysis of real-time reverse transcription polymerase chain reaction (RT–qPCR).

Results: Patients with grade II-IV GvHD exhibited lower median transcriptional levels of KIR genes compared to those with grade 0-I GvHD. In the GvHD group, aKIRs exhibited a more pronounced decrease of transcriptional levels, notably for the KIR2DS1, KIR2DS4, and KIR2DS5. Donors with the Bx genotype and a higher number of aKIRs showed a significant association with lower GvHD incidence. Multivariate analysis revealed that the donor KIR3DL1 non-recognition of the recipient HLA-Bw4, — specifically in HLA-Bw6 homozygous recipients, exhibited a trend toward increased risk of aGVHD compared to the recognition group. Further stratification into Group A (KIR3DL1-Bw4 non-recognition and low donor aKIR count) versus Group B (Bw4 recognition and high aKIR count) demonstrated a significantly higher incidence of GvHD in Group A (69.2% vs 43.1%, P= 0.008).

Conclusion: Our data suggest that aKIRs exhibited a more pronounced reduction in transcriptional levels within the GvHD group compared to iKIRs. The concomitant presence of low aKIR count and KIR3DL1-mediate non-recognition of Bw4 significantly increased the risk of GvHD. These findings provide useful insights into how KIR/HLA ligand interactions regulate NK cell alloreactivity in graft-versus-host responses.