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KIR Gene Mismatching and KIR/C Ligands in Liver Transplantation: Consequences for Short-Term Liver Allograft Injury

Legaz, Isabel1; López-Álvarez, María R.1; Campillo, José A.1; Moya-Quiles, María R.1; Bolarín, José M.1; de la Peña, Jesus2; Salgado, Gema1; Gimeno, Lourdes1; García-Alonso, Ana M.1; Muro, Manuel1; Miras, Manuel1,3; Alonso, Clara4; Álvarez-López, María R.1; Minguela, Alfredo1,5

doi: 10.1097/TP.0b013e318286486c
Clinical and Translational Research

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.

Supplemental digital content is available in the article.

1 Immunology Service, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas and Instituto Murciano de Investigación Biomédica, Murcia, Spain.

2 Pathology Service, University Hospital Virgen de la Arrixaca, Murcia, Spain.

3 Digestive Medicine Service, University Hospital Virgen de la Arrixaca, Murcia, Spain.

4 Immunology Service, University Hospital Juan Canalejo, La Coruña, Spain.

5 Address correspondence to: Alfredo Minguela, Servicio de Inmunología, University Hospital Virgen de la Arrixaca, Carretera Madrid-Cartagena, s/n 30120 El Palmar, Murcia, Spain.

This work was supported by the CIBERehd program; the projects 04087/GERM/06, Séneca Fundación, Consejería de Empresas y Universidades, Murcia; 10/1964, Fondo de Investigación Sanitaria del Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain; and Caja Murcia 2009–2010 aiding. The research works of I.L. was financed by the Sara Borrell Program from the Fondo de Investigación Sanitaria del Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain; and M.R.L.-A., by the CIBERehd Program; Séneca Fundación 04087/GERM/06 Project; and Programa Nacional de Movilidad de Recursos Humanos, Plan Nacional de I+D+i 2008–2011, Ministerio de Educación.

The authors declare no conflicts of interest.


I.L. and M.R.L.-A. contributed equally to the experimental work. J.A.C., M.R.M.-Q., G.S., and M.M. participated in some experiments or assays. J.P. was responsible for histologic acute rejection diagnosis. M.M. and C.A. provided patients and clinical data. J.M.B. and L.G. participated in collecting data and in statistical analysis. A.M.G.-A., M.R.A., and A.M. participated in making the experimental design. I.L., A.M. and M.R.A.-L. participated in writing the manuscript.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (

Received 8 October 2012. Revision requested 5 November 2012.

Accepted 4 January 2013.

© 2013 Lippincott Williams & Wilkins, Inc.