Killer Cell Immunoglobulin-like Receptors (KIR) and Human Leucocyte Antigen C (HLA-C) Increase the Risk of Long-Term Chronic Liver Graft Rejection

Chronic liver rejection (CR) represents a complex clinical situation because many patients do not respond to increased immunosuppression. Killer cell immunoglobulin-like receptors/Class I Human Leukocyte Antigens (KIR/HLA-I) interactions allow for predicting Natural Killer (NK) cell alloreactivity and influence the acute rejection of liver allograft. However, its meaning in CR liver graft remains controversial. KIR and HLA genotypes were studied in 513 liver transplants using sequence-specific oligonucleotides (PCR-SSO) methods. KIRs, human leucocyte antigen C (HLA-C) genotypes, KIR gene mismatches, and the KIR/HLA-ligand were analyzed and compared in overall transplants with CR (n = 35) and no-chronic rejection (NCR = 478). Activating KIR (aKIR) genes in recipients (rKIR2DS2(+) and rKIR2DS3(+)) increased CR compared with NCR groups (p = 0.013 and p = 0.038). The inhibitory KIR (iKIR) genes in recipients rKIR2DL2(+) significantly increased the CR rate compared with their absence (9.1% vs. 3.7%, p = 0.020). KIR2DL3 significantly increases CR (13.1% vs. 5.2%; p = 0.008). There was no influence on NCR. CR was observed in HLA-I mismatches (MM). The absence of donor (d) HLA-C2 ligand (dC2(-)) ligand increases CR concerning their presence (13.1% vs. 5.6%; p = 0.018). A significant increase of CR was observed in rKIR2DL3(+)/dC1(-) (p = 0.015), rKIR2DS4/dC1(-) (p = 0.014) and rKIR2DL3(+)/rKIR2DS4(+)/dC1(-) (p = 0.006). Long-term patient survival was significantly lower in rKIR2DS1(+)rKIR2DS4(+)/dC1(-) at 5-10 years post-transplant. This study shows the influence of rKIR/dHLA-C combinations and aKIR gene-gene mismatches in increasing CR and KIR2DS1(+)/C1-ligands and the influence of KIR2DS4(+)/C1-ligands in long-term graft survival.

Automated summary

This study reveals that the combination of activating killer cell immunoglobulin-like receptor (KIR) genes and European human leukocyte antigen 2 (HLA-C2) genotypes in recipients is associated with chronic liver rejection (CR). The presence of inhibitory KIR genes significantly increases the incidence of chronic rejection. In addition, KIR2DL3 and the absence of donor HLA-C2 ligand also have an impact on chronic rejection. These findings have important clinical implications for understanding the mechanism of chronic liver rejection and improving treatment options.