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 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.