HLA variants related to primary sclerosing cholangitis influence rejection after liver transplantation

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 included143 adult donor-recipient pairs with a minimum of 6mo 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*07and 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*08homozygous 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,HLADRB1*03 and HLA-DRB1*04 alleles and risk of AR in liver transplant recipients.