Original Article
Copyright ©2014 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Apr 14, 2014; 20(14): 3986-4000
Published online Apr 14, 2014. doi: 10.3748/wjg.v20.i14.3986
HLA variants related to primary sclerosing cholangitis influence rejection after liver transplantation
Bjarte Fosby, Sigrid Næss, Johannes R Hov, James Traherne, Kirsten M Boberg, John Trowsdale, Aksel Foss, Pål-Dag Line, Andre Franke, Espen Melum, Helge Scott, Tom H Karlsen
Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway
Bjarte Fosby, Sigrid Næss, Johannes R Hov, Aksel Foss, Espen Melum, Kirsten Muri Boberg, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0318 Oslo, Norway
Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Helge Scott, Tom H Karlsen, KG Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, N-0424 Oslo, Norway
Johannes R Hov, Kirsten M Boberg, Aksel Foss, Pål-Dag Line, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway
James Traherne, John Trowsdale, Division of Immunology, Department of Pathology, University of Cambridge and Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 1TN, United Kingdom
Andre Franke, Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24118 Kiel, Germany
Helge Scott, Department of Pathology, Divisoin of Diagnostics and Intervention, Institute of Pathology, Oslo University Hospital, N-0027 Oslo, Norway
Author contributions: Fosby B, Scott H and Karlsen TH conceived and designed the study; Fosby B, Boberg KM, Foss A, Line PD and Karlsen TH recruited the study subjects; Fosby B, Næss S, Traherne J, Trowsdale J, Franke A, Scott H and Karlsen TH performed the genotyping and immunohistochemistry; Fosby B, Næss S, Hov JR, Traherne J, Trowsdale J, Melum E, Scott H and Karlsen TH analyzed the data; Fosby B wrote the manuscript; all authors have read and approved the final manuscript prior to publication.
Supported by Norwegian PSC Research Center; the Wellcome Trust and the MRC with additional support from the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (to Traherne J and Trowsdale J)
Correspondence to: Tom H Karlsen, MD, PhD, Professor, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, N-0424 Oslo, Norway. t.h.karlsen@medisin.uio.no
Telephone: +47-230-72469 Fax: +47-230-73510
Received: January 30, 2014
Revised: February 11, 2014
Accepted: March 7, 2014
Published online: April 14, 2014

AIM: To investigate influence of human leukocyte antigen (HLA) and killer immunoglobuline-like receptor (KIR) genotypes on risks of acute rejection (AR) after liver transplantation (LTX).

METHODS: In this retrospective study we included 143 adult donor-recipient pairs with a minimum of 6 mo follow-up after LTX for whom DNA was available from both donor and recipients. Clinical data, all early complications including episodes and severity of AR and graft/patient survival were registered. The diagnosis of AR was based on clinical, biochemical and histological criteria. All suspected episodes of AR were biopsy confirmed. Key classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped using Sanger sequencing. 16 KIR genes were genotyped using a novel real time PCR approach which allows for determination of the diploid copy number of each KIR gene. Immunohistochemical staining for T (CD3), B (CD20) and natural killer (NK) cells (CD56 and CD57) were performed on liver biopsies from 3 different patient groups [primary sclerosing cholangitis (PSC), primary biliary cirrhosis and non-autoimmune liver disease], 10 in each group, with similar grade of AR.

RESULTS: Fourty-four (31%) patients were transplanted on the basis of PSC, 40% of them had AR vs 24% in the non-PSC group (P = 0.04). No significant impact of donor-recipient matching for HLA and KIR genotypes was detected. In the overall recipient population an increased risk of AR was detected for HLA-B*08 (P = 0.002, OR = 2.5; 95%CI: 1.4-4.6), HLA-C*07 (P = 0.001, OR = 2.4; 95%CI: 1.4-4.0) and HLA-DRB1*03 (P = 0.03, OR = 1.9; 95%CI: 1.0-3.3) and a decreased risk for HLA-DRB1*04 (P = 0.001, OR = 0.2; 95%CI: 0.1-0.5). For HLA-B*08, HLA-C*07 and DRB1*04 the associations remained evident in a subgroup analysis of non-PSC recipients (P = 0.04, P = 0.003 and P = 0.02, respectively). In PSC recipients corresponding P values were 0.002, 0.17 and 0.01 for HLA-B*08, HLA-C*07 and DRB1*04, respectively. A dosage effect of AR prevalence according to the PSC associated HLA alleles was also notable in the total recipient population. For HLA-B*08 the frequency of AR was 56% in HLA-B*08 homozygous recipients, 39% in heterozygous recipients and 21% in recipients lacking HLA-B*08 (P = 0.02). The same was observed for the HLA-C*07 allele with AR in 57%, 27% and 18% in recipients being homozygous, heterozygous and lacking HLA-C*07 respectively (P = 0.003). Immunohistochemical analysis showed similar infiltration of T, B and NK cells in biopsies with AR in all three groups.

CONCLUSION: We found significant associations between the PSC-associated HLA-B*08, HLA-C*07, HLA-DRB1*03 and HLA-DRB1*04 alleles and risk of AR in liver transplant recipients.

Keywords: Liver transplantation, Primary sclerosing cholangitis, Acute rejection, Human leukocyte antigen, Killer immunoglobulin-like receptor

Core tip: Patients undergoing liver transplantation on the basis of primary sclerosing cholangitis (PSC) have a higher frequency of acute cellular rejections than non-PSC patients. Recent studies have determined the genetic susceptibility to PSC, of which genetic variants in the human leukocyte antigen complex represent the strongest risk factors. In the present report we show that these variants also influence risk of acute cellular rejection after liver transplantation in PSC. Moreover, we show that the same variants also involve in risk of acute cellular rejection in non-PSC recipients.