Donor and recipient HLA/KIR genotypes do not predict liver transplantation outcome

Abstract

Summary Whether or not Natural Killer (NK) cells affect the immune response to solid organ allografts is still controversial. Main determinants of NK‐cell activation are specific HLA/killer‐cell immunoglobulin‐like receptors (KIR) interactions that, in transplantation, may induce NK‐cell alloreactivity. So far, in liver transplantation (LTX) donor‐versus‐recipient alloreactivity has not been investigated; in addition, studies of predicted recipient‐versus‐donor NK‐cell alloreactivity have led to contradicting results. We typed a cohort of LTX donors and recipients for HLA‐C/Bw4 and KIRs. We estimated the effect of NK‐cell alloreactivity, as predicted by classically used models, in the donor‐versus‐recipient direction. The results indicate that HLA/KIR mismatches in the donor‐versus‐recipient direction do not predict graft rejection nor graft or patient survival, suggesting that donor‐derived NK cells do not play a major role in LTX outcome. In addition, when considering predicted NK‐cell alloreactivity in the reverse direction (recipient‐versus‐donor), we first confirmed that donor HLA‐C genotype was not associated with acute rejection, graft or patient survival and secondly we found that none of the models describing NK‐cell alloreactivity could predict LTX outcome. Overall our observations suggest that, in contrast to what is shown in haematopoietic stem cell transplantation, donor‐derived NK cells may not contribute in preventing liver graft rejection, and that recipient‐versus‐donor NK‐cell alloreactivity does not predict LTX outcome.

Human Leukocyte Antigen-C Genotype and Killer Immunoglobulin-like Receptor-Ligand Matching in Korean Living Donor Liver Transplantation

“…Our results support the previous studies suggesting that the KIR2DL1/S1+ allogeneic T cell subset, which is specific for donor C2 ligands, may be induced, or the binding of aKIR (KIR2DS1) to a donor HLA-C2 ligand can induce alloreactivity [2122]. However, other studies demonstrated controversial data showing no impact of donor HLA-C2 genotype on graft or patient survival [91419]. HLA-C proteins may act as alloantigens, which can induce T cell activation and may also function as ligands for KIRs, modulating NK and T cell cytotoxicity [9].…”

“…The ethnic differences between the previous study and our data appeared to be due to the underlying cause of LT and the type of donor. In Korea, the predominant disease necessitating LT is hepatitis B virus (HBV)-related liver disease, but in Western countries, hepatitis C virus (HCV)-related liver disease and autoimmunity account for a considerable proportion along with viral hepatitis [1119]. Although direct influence of the underlying disease on clinical outcome was not sufficient, different underlying diseases may affect patient NK cell function.…”

“…For AB and BB genotypes, if the AA genotype was excluded and 2DS4 was absent, the BB genotype was assigned, and the others were designated as AB. To predict NK alloreactivity, we evaluated two main models: the 'ligand-ligand' or 'missing-self' model, and the 'receptor-ligand' or 'missing-ligand' model [581920]. 'Missing-self model' was defined as KIR-ligand mismatching between the donor and recipient, and the effect of HLA-C ligand compatibility on the liver allograft outcome was investigated.…”

Natural Killer Cells in Liver Disease

“…One study of 100 transplants showed that matching of the main HLA ligand recognised by NK cells, HLA-C, between donor and recipient, reduced the likelihood of acute rejection, with recipients who expressed no HLA-C group 2 alleles further protected from acute rejection [131]. However, later, larger studies were unable to replicate these results [132,133]. A study of HLA-C effect on chronic rejection of 595 liver transplants showed that the presence of at least one HLA-C group 2 allele in the donor was protective [132], but again this finding could not be replicated in a later study [133].…”

Natural Killer Cells and Liver Transplantation: Orchestrators of Rejection or Tolerance?

“…However, studies of KIR-HLA class I mismatch have not conclusively correlated with graft rejection or survival. The value of HLA-C-KIR typing in predicting recipientversus-donor and donor-versus-recipient reactions has been investigated in a cohort of 348 LT patients (38). Using predictive models of NK cell alloreactivity, no correlation between HLA-C-KIR mismatch and liver transplant outcome was found.…”