title: KIR gene mismatching and KIR/C ligands in liver transplantation: consequences for short-term liver allograft injury.
abstract: BACKGROUND
  Killer immunoglobulin-like receptors (KIRs) bind human leukocyte antigen (HLA) class-I (HLA-I) ligands and regulate functions of natural killer cells and subsets of T cells. KIR/HLA-I interactions allow predicting natural killer cell alloreactivity in hematopoietic stem cell transplantation and in HLA-compatible kidney transplants, but its meaning in liver transplantation remains controversial.
  
  
  METHODS
  KIR and HLA genotypes were studied in 402 liver transplants, using sequence-specific oligonucleotides and primer methods. Recipients and donor KIRs, HLA-C genotypes, KIR gene mismatches (MMs) between recipient-donor pairs, and KIR/HLA-ligand combinations were analyzed in overall transplantations, in the acute rejection (AR; n=110) and non-AR (n=292) groups.
  
  
  RESULTS
  KIR gene MMs between recipients and donors, mainly in activating KIRs, and KIR2DL3 and KIR2DS1 of recipients in the presence of donor C2 ligands, significantly enhanced early AR rate (P<0.05), with KIR2DL3 and KIR2DS1 exhibiting a synergic effect in dependence of the donor C2 ligand number (χ2=7.662, P=0.022). KIR2DL3, KIR2DS1, and also KIR2DS4 significantly influenced short-term graft survival, with a benefit for transplantations combining KIR2DL3 recipients and donors having C1 ligands (log rank, P<0.019 at 1 year; hazards ratio [HR], 0.321; 95% confidence interval [CI], 0.107-0.962; P=0.042), whereas KIR2DS1 and KIR2DS4 recipients combined with donors lacking C1 ligands (C2/C2) exhibited a worse graft survival (log rank, P=0.035 at 6 months; HR, 7.713; 95% CI, 2.156-27.369; P=0.002 for KIR2DS1; and log rank, P=0.006 at 1 year; HR, 3.794; 95% CI, 1.267-11.365; P=0.017 for KIR2DS4).
  
  
  CONCLUSIONS
  This study shows that KIR gene-gene MMs increase AR and that KIRs/C ligands associated to AR and KIR2DS4/C ligands also influence short-term graft survival.
authors.affiliation: Immunology Service, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas and Instituto Murciano de Investigación Biomédica, Murcia, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Legaz
authors.forename: María R
authors.initials: MR
authors.lastname: López-Álvarez
authors.forename: José A
authors.initials: JA
authors.lastname: Campillo
authors.forename: María R
authors.initials: MR
authors.lastname: Moya-Quiles
authors.forename: José M
authors.initials: JM
authors.lastname: Bolarín
authors.forename: Jesus
authors.initials: J
authors.lastname: de la Peña
authors.forename: Gema
authors.initials: G
authors.lastname: Salgado
authors.forename: Lourdes
authors.initials: L
authors.lastname: Gimeno
authors.forename: Ana M
authors.initials: AM
authors.lastname: García-Alonso
authors.forename: Manuel
authors.initials: M
authors.lastname: Muro
authors.forename: Manuel
authors.initials: M
authors.lastname: Miras
authors.forename: Clara
authors.initials: C
authors.lastname: Alonso
authors.forename: María R
authors.initials: MR
authors.lastname: Álvarez-López
authors.forename: Alfredo
authors.initials: A
authors.lastname: Minguela
mesh_terms: D015331:Cohort Studies; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D015236:HLA-C Antigens / Q000378:metabolism; D006526:Hepatitis C / Q000209:etiology / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008024:Ligands; D016031:Liver Transplantation / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D054340:Receptors, KIR / Q000235:genetics*; D054344:Receptors, KIR2DL3 / Q000235:genetics; D012008:Recurrence; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013997:Time Factors
chemical_list: D015236:HLA-C Antigens; C515078:KIR2DL3 protein, human; C496212:KIR2DS1 protein, human; D008024:Ligands; D054340:Receptors, KIR; D054344:Receptors, KIR2DL3