title: Donor HLA-C genotype has a profound impact on the clinical outcome following liver transplantation.
abstract: Late allograft dysfunction is a significant problem following liver transplantation and its pathogenesis is uncertain. HLA-C is the major inhibitory ligand for killer immunoglobulin-like receptors (KIRs) that regulate the cytotoxic activity of natural killer (NK) cells. HLA-C alleles can be allocated into two groups, termed HLA-C1 and HLA-C2, based on their KIR specificity. HLA-C2 interactions are more inhibiting to NK cell activation. We studied the clinical importance of HLA-C genotype in a large liver transplant cohort and found that possession of at least one HLA-C2 allele by the donor allograft was associated with less histological evidence of chronic rejection and graft cirrhosis, a 16.2% reduction in graft loss (p = 0.003) (hazard ratio: 2.7, 95% CI 1.4-5.3) and a 13.6% improvement in patient survival (p = 0.01) (hazard ratio: 1.9, 95% CI 1.1-3.3) at 10 years. Transplantation of an HLA-C2 homozygous allograft led to a particularly striking 26.5% reduction in graft loss (p < 0.001) (hazard ratio: 7.2, 95% CI 2.2-23.0) at 10 years when compared to HLA-C1 homozygous allografts. Donor HLA-C genotype is therefore a major determinant of clinical outcome after liver transplantation and reveals the importance of NK cells in chronic rejection and graft cirrhosis. Modulation of HLA-C and KIR interactions represents an important novel approach to promote long-term graft and patient survival.
authors.affiliation: Department of Nephrology & Transplantation, University Hospital Birmingham, Edgbaston, Birmingham, UK. rhanvesakul@doctors.org.uk
authors.forename: R
authors.initials: R
authors.lastname: Hanvesakul
authors.forename: N
authors.initials: N
authors.lastname: Spencer
authors.forename: M
authors.initials: M
authors.lastname: Cook
authors.forename: B
authors.initials: B
authors.lastname: Gunson
authors.forename: M
authors.initials: M
authors.lastname: Hathaway
authors.forename: R
authors.initials: R
authors.lastname: Brown
authors.forename: P
authors.initials: P
authors.lastname: Nightingale
authors.forename: P
authors.initials: P
authors.lastname: Cockwell
authors.forename: S G
authors.initials: SG
authors.lastname: Hubscher
authors.forename: D H
authors.initials: DH
authors.lastname: Adams
authors.forename: P
authors.initials: P
authors.lastname: Moss
authors.forename: D
authors.initials: D
authors.lastname: Briggs
mesh_terms: D000328:Adult; D000483:Alleles; D015331:Cohort Studies; D005260:Female; D005355:Fibrosis / Q000453:epidemiology / Q000473:pathology; D005500:Follow-Up Studies; D005838:Genotype; D006084:Graft Rejection / Q000453:epidemiology* / Q000473:pathology; D006085:Graft Survival / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics*; D006579:Heterozygote; D006650:Histocompatibility Testing; D006720:Homozygote; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D015999:Multivariate Analysis; D054340:Receptors, KIR / Q000276:immunology; D016019:Survival Analysis; D013997:Time Factors; D014019:Tissue Donors; D016896:Treatment Outcome; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D015236:HLA-C Antigens; D054340:Receptors, KIR