Donor HLA-C genotype has a profound impact on the clinical outcome following liver transplantation.
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.
Hanvesakul
R
R
Department of Nephrology & Transplantation, University Hospital Birmingham, Edgbaston, Birmingham, UK. rhanvesakul@doctors.org.uk
Spencer
N
N
Cook
M
M
Gunson
B
B
Hathaway
M
M
Brown
R
R
Nightingale
P
P
Cockwell
P
P
Hubscher
S G
SG
Adams
D H
DH
Moss
P
P
Briggs
D
D
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
D015236:HLA-C Antigens; D054340:Receptors, KIR