జర్నల్ ఆఫ్ ఫోరెన్సిక్ మెడిసిన్

Association between Immunoglobulin Receptors, Antigen C and Elevated Risk of Chronic Liver Rejection

Abstract

Miguel Bolarín

Chronic liver rejection poses a complex challenge in transplantation, as some patients do not respond to increased immunosuppression. Killer cell immunoglobulin-like receptors and their interactions with Class I Human Leukocyte Antigens (HLA-I) play a crucial role in predicting Natural Killer (NK) cell alloreactivity and influencing acute liver graft rejection. However, their relevance in CR remains a subject of debate. In this study, we investigated KIR and HLA genotypes in 513 liver transplant recipients using sequence-specific oligonucleotide (PCR-SSO) methods. We examined KIRs, human leukocyte antigen C (HLA-C) genotypes, KIR gene combinations, and KIR/HLA ligand interactions in the entire cohort and compared them between CR (n=35) and no-ongoing rejection (NCR=478) cases. It was found that the presence of activating KIR (aKIR) genes in recipients (rKIR2DS2+ and rKIR2DS3+) increased the risk of CR compared to the NCR group (p=0.013 and p=0.038). Inhibitory KIR (iKIR) genes in recipients, particularly rKIR2DL2+, significantly elevated the CR rate compared to their absence (9.1% versus 3.7%, p=0.020), and KIR2DL3 also had a significant impact on increasing CR (13.1% versus 5.2%; p=0.008), with no effect on NCR. Furthermore, CR was observed in cases with HLA-I mismatches (MM), and the absence of the donor (d) HLA-C2 ligand (dC2−) increased the risk of CR compared to its presence (13.1% versus 5.6%; p=0.018). A significant increase in CR was noted in cases with rKIR2DL3+/dC1− (p=0.015), rKIR2DS4/dC1− (p=0.014), and rKIR2DL3+/ rKIR2DS4+/dC1− (p=0.006) combinations. Long-term patient survival was significantly lower in recipients with rKIR2DS1+rKIR2DS4+/dC1− at 5-10 years post-transplant. This study highlights the influence of rKIR/dHLA-C combinations and aKIR gene variations in increasing the risk of CR, as well as the impact of KIR2DS1+/C1-ligands and KIR2DS4+/C1-ligands on long-term graft survival.